2-pyridone derivatives as neutrophil elastase inhibitors and their use

ABSTRACT

There are provided novel compounds of formula (I), 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 4 , G 1 , G 2 , L, Y and n are as defined in the Specification and optical isomers, racemates and tautomers thereof, and pharmaceutically acceptable salts thereof; together with processes for their preparation, compositions containing them and their use in therapy. The compounds are inhibitors of neutrophil elastase.

FIELD OF THE INVENTION

This invention relates to novel 2-pyridone derivatives, processes fortheir preparation, pharmaceutical compositions comprising them, andtheir use in therapy.

BACKGROUND OF THE INVENTION

Elastases are possibly the most destructive enzymes in the body, havingthe ability to degrade virtually all connective tissue components. Theuncontrolled proteolytic degradation by elastases has been implicated ina number of pathological conditions. Human neutrophil elastase (hNE), amember of the chymotrypsin superfamily of serine proteases is a 33-KDaenzyme stored in the azurophilic granules of the neutrophils. Inneutrophils the concentration of NE exceeded 5 mM and its total cellularamount has been estimated to be up to 3 pg. Upon activation, NE israpidly released from the granules into the extracellular space withsome portion remaining bound to neutrophil plasma membrane (See Kawabatet al. 2002, Eur. J. Pharmacol. 451, 1-10). The main intracellularphysiological function of NE is degradation of foreign organic moleculesphagocytosed by neutrophils, whereas the main target for extracellularelastase is elastin (Janoff and Scherer, 1968, J. Exp. Med. 128,1137-1155). NE is unique, as compared to other proteases (for example,proteinase 3) in that it has the ability to degrade almost allextracellular matrix and key plasma proteins (See Kawabat et al., 2002,Eur. J. Pharmacol. 451, 1-10). It degrades a wide range of extracellularmatrix proteins such as elastin, Type 3 and type 4 collagens, laminin,fibronectin, cytokines, etc. (Ohbayashi, H., 2002, Expert Opin.Investig. Drugs, 11, 965-980). NE is a major common mediator of manypathological changes seen in chronic lung disease including epithelialdamage (Stockley, R. A. 1994, Am. J. Resp. Crit. Care Med. 150,109-113).

The destructive role of NE was solidified almost 40 years ago whenLaurell and Eriksson reported an association of chronic airflowobstruction and emphysema with deficiency of serum α₁-antitrypsin(Laurel and Eriksson, 1963, Scand. J. Clin. Invest. 15, 132-140).Subsequently it was determined that α₁-antitrypsin is the most importantendogenous inhibitor of human NE. The imbalance between human NE andendogenous antiprotease is believed to cause excess human NE inpulmonary tissues which is considered as a major pathogenic factor inchronic obstructive pulmonary disease (COPD). The excessive human NEshows a prominent destructive profile and actively takes part indestroying the normal pulmonary structures, followed by the irreversibleenlargement of the respiratory airspaces, as seen mainly in emphysema.There is an increase in neutrophil recruitment into the lungs which isassociated with increased lung elastase burden and emphysema inα₁-proteinase inhibitor-deficient mice (Cavarra et al., 1996, Lab.Invest. 75, 273-280). Individuals with higher levels of the NE-α₁protease inhibitor complex in bronchoalveolar lavage fluid showsignificantly accelerated decline in lung functions compared to thosewith lower levels (Betsuyaku et al. 2000, Respiration, 67, 261-267).Instillation of human NE via the trachea in rats causes lunghaemorrhage, neutrophil accumulation during acute phase andemphysematous changes during chronic phase (Karaki et al., 2002, Am. J.Resp. Crit. Care Med., 166, 496-500). Studies have shown that the acutephase of pulmonary emphysema and pulmonary haemorrhage caused by NE inhamsters can be inhibited by pre-treatment with inhibitors of NE (Fujieet al., 1999, Inflamm. Res. 48, 160-167).

Neutrophil-predominant airway inflammation and mucus obstruction of theairways are major pathologic features of COPD, including cystic fibrosisand chronic bronchitis. NE impairs mucin production, leading to mucusobstruction of the airways. NE is reported to increase the expression ofmajor respiratory mucin gene, MUC5AC (Fischer, B. M. & Voynow, 2002, Am.J. Respir. Cell Biol., 26, 447-452). Aerosol administration of NE toguinea pigs produces extensive epithelial damage within 20 minutes ofcontact (Suzuki et al., 1996, Am. J. Resp. Crit. Care Med., 153,1405-1411). Furthermore NE reduces the ciliary beat frequency of humanrespiratory epithelium in vitro (Smallman et al., 1984, Thorax, 39,663-667) which is consistent with the reduced mucociliary clearance thatis seen in COPD patients (Currie et al., 1984, Thorax, 42, 126-130). Theinstillation of NE into the airways leads to mucus gland hyperplasia inhamsters (Lucey et al., 1985, Am. Resp. Crit. Care Med., 132, 362-366).A role for NE is also implicated in mucus hypersecretion in asthma. Inan allergen sensitised guinea pig acute asthma model an inhibitor of NEprevented goblet cell degranulation and mucus hypersecretion (Nadel etal., 1999, Eur. Resp. J., 13, 190-196).

NE has been also shown to play a role in the pathogenesis of pulmonaryfibrosis. NE: α₁-protenase inhibitor complex is increased in serum ofpatients with pulmonary fibrosis, which correlates with the clinicalparameters in these patients (Yamanouchi et al., 1998, Eur. Resp. J. 11,120-125). In a murine model of human pulmonary fibrosis, a NE inhibitorreduced bleomycin-induced pulmonary fibrosis (Taooka et al., 1997, Am.J. Resp. Crit. Care Med., 156, 260-265). Furthermore investigators haveshown that NE deficient mice are resistant to bleomycin-inducedpulmonary fibrosis (Dunsmore et al., 2001, Chest, 120, 35S-36S). PlasmaNE level was found to be elevated in patients who progressed to ARDSimplicating the importance of NE in early ARDS disease pathogenesis.(Donnelly et al., 1995, Am. J. Res. Crit. Care Med., 151, 4284433). Theantiproteases and NE complexed with antiprotease are increased in lungcancer area (Marchandise et al., 1989, Eur. Resp. J. 2, 623-629). Recentstudies have shown that polymorphism in the promoter region of the NEgene are associated with lung cancer development (Taniguchi et al.,2002, Clin. Cancer Res., 8, 1115-1120.

Acute lung injury caused by endotoxin in experimental animals isassociated with elevated levels of NE (Kawabata, et al., 1999, Am. J.Resp. Crit. Care, 161, 2013-2018). Acute lung inflammation caused byintratracheal injection of lipopolysaccharide in mice has been shown toelevate the NE activity in bronchoalveolar lavage fluid which issignificantly inhibited by a NE inhibitor (Fujie et al., 1999, Eur. J.Pharmacol., 374, 117-125; Yasui, et al., 1995, Eur. Resp. J., 8,1293-1299). NE also plays an important role in the neutrophil-inducedincrease of pulmonary microvascular permeability observed in a model ofacute lung injury caused by tumour necrosis factor α (TNFα) and phorbolmyristate acetate (PMA) in isolated perfused rabbit lungs (Miyazaki etal., 1998, Am. J. Respir. Crit. Care Med., 157, 89-94).

A role for NE has also been suggested in monocrotoline-induced pulmonaryvascular wall thickening and cardiac hypertrophy (Molteni et al., 1989,Biochemical Pharmacol. 38, 2411-2419). Serine elastase inhibitorreverses the monocrotaline-induced pulmonary hypertension andremodelling in rat pulmonary arteries (Cowan et al., 2000, NatureMedicine, 6, 698-702). Recent studies have shown that serine elastase,that is, NE or vascular elastase are important in cigarettesmoke-induced muscularisation of small pulmonary arteries in guinea pigs(Wright et al., 2002, Am. J. Respir. Crit. Care Med., 166, 954-960).

NE plays a key role in experimental cerebral ischemic damage (Shimakuraet al., 2000, Brain Research, 858, 55-60), ischemia-reperfusion lunginjury (Kishima et al., 1998, Ann. Thorac. Surg. 65, 913-918) andmyocardial ischemia in rat heart (Tiefenbacher et al., 1997, Eur. J.Physiol., 433, 563-570). Human NE levels in plasma are significantlyincreased above normal in inflammatory bowel diseases, for example,Crohn's disease and ulcerative colitis (Adeyemi et al., 1985, Gut, 26,1306-1311). In addition NE has also been assumed to be involved in thepathogenesis of rheumatoid arthritis (Adeyemi et al., 1986, Rheumatol.Int., 6, 57). The development of collagen induced arthritis in mice issuppressed by a NE inhibitor (Kakimoto et al., 1995, Cellular Immunol.165, 26-32).

Thus, human NE is known as one of the most destructive serine proteasesand has been implicated in a variety of inflammatory diseases. Theimportant endogenous inhibitor of human NE is α₁-antitrypsin. Theimbalance between human NE and antiprotease is believed to give rise toan excess of human NE resulting in uncontrolled tissue destruction. Theprotease/antiprotease balance may be upset by a decreased availabilityof α₁-antitrypsin either through inactivation by oxidants such ascigarette smoke, or as a result of genetic inability to producesufficient serum levels. Human NE has been implicated in the promotionor exacerbation of a number of diseases such as pulmonary emphysema,pulmonary fibrosis, adult respiratory distress syndrome (ARDS), ischemiareperfusion injury, rheumatoid arthritis and pulmonary hypertension.

WO 02/053543 discloses pyridone derivatives having affinity forcannabinoid 2-type receptor.

The present invention discloses novel 2-pyridione derivatives that areinhibitors of human neutrophil elastase and homologous serine proteasessuch as proteinase 3 and pancreatic elastase, and are thereby useful intherapy.

DISCLOSURE OF THE INVENTION

The present invention provides a compound of formula (I)

wherein:Y represents CR³ or N;R¹ represents H or C1 to 6 alkyl;R² represents phenyl or a five- or six-membered heteroaromatic ringcontaining 1 to 4 heteroatoms independently selected from O, S and N;said aromatic ring being optionally substituted by 1 to 3 substituentsselected independently from OH, halogen, C1 to 6 alkyl, C1 to 6 alkoxy,NR⁵⁸COR⁵⁰, COOR⁵¹, COR⁵², CONR⁵³R⁵⁴ and NR⁴⁷R⁴⁸; said alkyl beingoptionally further substituted by OH, C1 to 6 alkoxy, CN or CO₂R⁴⁹;R⁴⁷ and R⁴⁸ independently represent H, C1 to 6 alkyl or C2 to 6alkanoyl;R³ represents H or F;G¹ represents phenyl or a five- or six-membered heteroaromatic ringcontaining 1 to 3 heteroatoms independently selected from O, S and N;R⁵ represents H, halogen, C1 to 6 alkyl, CN, C1 to 6 alkoxy, NO₂,NR¹⁴R¹⁵, C1 to 3 alkoxy substituted by one or more F atoms or C1 to 3alkoxy substituted by one or more F atoms;R¹⁴ and R¹⁵ independently represent H or C1 to 3 alkyl; said alkyl beingoptionally further substituted by one or more F atoms;n represents an integer 1, 2 or 3 and when n represents 2 or 3, each R⁵group is selected independently;R⁴ represents H or C1 to 6 alkyl; said alkyl being optionally furthersubstituted by OH or C1 to 6 alkoxy;or R⁴ and L are joined together such that the group —NR⁴L represents a 5to 7 membered azacyclic ring optionally incorporating one furtherheteroatom selected from O, S and NR¹⁶;L represents a bond, O, S(O)p, NR²⁹ or C1 to 6 alkyl; said alkyloptionally incorporating a heteroatom selected from O, S and NR¹⁶; andsaid alkyl being optionally further substituted by OH or OMe;G² represents a monocyclic ring system selected from:

-   i) phenyl or phenoxy,-   ii) a 5 or 6 membered heteroaromatic ring containing one to three    heteroatoms independently selected from O, S and N,-   iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or-   iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring    containing one or two heteroatoms independently selected from O,    S(O)_(p) and NR¹⁷ and optionally further incorporating a carbonyl    group; or    G² represents a bicyclic ring system in which each of the two rings    is independently selected from:-   i) phenyl,-   ii) a 5 or 6 membered heteroaromatic ring containing one to three    heteroatoms independently selected from O, S and N,-   iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or-   iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring    containing one or two heteroatoms independently selected from O,    S(O)_(p) and NR¹⁷ and optionally further incorporating a carbonyl    group;    and the two rings are either fused together, or are bonded directly    together or are separated by a linker group selected from O,    S(O)_(q) or CH₂,    said monocyclic or bicyclic ring system being optionally further    substituted by one to three substituents independently selected from    CN, OH, C1 to 6 alkyl, C1 to 6 alkoxy, halogen, NR¹⁸R¹⁹, NO₂,    OSO₂R³⁸, CO₂R²⁰, C(═NH)NH₂, C(O)NR²¹R²², C(S)NR²³R²⁴, SC(═NH)NH₂,    NR³¹C(═NH)NH₂, S(O)_(s)R²⁵, SO₂NR²⁶R²⁷, C1 to 3 alkoxy substituted    by one or more F atoms and C1 to 3 alkyl substituted by SO₂R³⁹,    NR⁵⁶R⁵⁷ or by one or more F atoms;    or    when L does not represent an bond, G² may also represent H;

At each occurrence, p, q, s and t independently represent an integer 0,1 or 2;

R¹⁸ and R¹⁹ independently represent H, C1 to 6 alkyl, formyl, C2 to 6alkanoyl, S(O)_(t)R³² or SO₂NR³³R³⁴; said alkyl group being optionallyfurther substituted by halogen, CN, C1 to 4 alkoxy or CONR⁴¹R⁴²;R²⁵ represents H, C1 to 6 alkyl or C3 to 6 cycloalkyl; said alkyl groupbeing optionally further substituted by one or more substituentsselected independently from OH, CN, CONR³⁵R³⁶, CO₂R³⁷, OCOR⁴⁰, C3 to 6cycloalkyl, a C4 to 7 saturated heterocyclic ring containing one or twoheteroatoms independently selected from O, S(O)_(p) and NR⁴³ and phenylor a 5 or 6 membered heteroaromatic ring containing one to threeheteroatoms is independently selected from O, S and N; said aromaticring being optionally further substituted by one or more substituentsselected independently from halogen, CN, C1 to 4 alkyl, C1 to 4 alkoxy,OH, CONR⁴⁴R⁴⁵, CO₂R⁴⁶, S(O)_(s)R⁵⁵ and NHCOCH₃;R³² represents H, C1 to 6 alkyl or C3 to 6 cycloalkyl;R¹⁶, R¹⁷, R²⁰, R²¹, R²², R²³, R²⁴, R²⁶, R²⁷, R²⁹, R³¹, R³³, R³⁴, R³⁵,R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁹, R⁵⁰, R⁵¹,R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷ and R⁵⁸ independently represent H or C1 to6 alkyl;and pharmaceutically acceptable salts thereof.

The compounds of formula (I) may exist in enantiomeric and/or tautomericforms. It is to be understood that all enantiomers, diastereomers,racemates, tautomers and mixtures thereof are included within the scopeof the invention.

Unless otherwise indicated, the term “C1 to 6 alkyl” referred to hereindenotes a straight or branched chain alkyl group having from 1 to 6carbon atoms. Examples of such groups include methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, t-butyl, pentyl and hexyl. The terms “C1 to3 alkyl” and “C1 to 4 alkyl” are to be interpreted analogously.

Examples of “C1 to 3 alkyl substituted by one or more F atoms” includefluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,1,1-difluoroethyl, pentafluoroethyl and 3,3,3-trifluoropropyl.

Unless otherwise indicated, the term “C1 to 6 alkoxy” referred to hereindenotes an oxygen substituent bonded to a straight or branched chainalkyl group having from 1 to 6 carbon atoms. Examples of such groupsinclude methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy ands-butoxy. The terms “C1 to 3 alkoxy” and “C1 to 4 alkoxy” are to beinterpreted analogously.

Examples of “C1 to 3 alkoxy substituted by one or more F atoms” includefluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy and3,3,3-trifluoropropoxy.

Unless otherwise indicated, the term “C2 to 6 alkanoyl” referred toherein denotes a straight or branched chain alkyl group having from 1 to5 carbon atoms bonded to the molecule via a carbonyl group. Examples ofsuch groups include acetyl, propionyl and pivaloyl.

Unless otherwise indicated, the term “halogen” referred to hereindenotes fluorine, chlorine, bromine and iodine.

Examples of a five or six membered heteroaromatic ring containing 1 to 4heteroatoms independently selected from O, S and N include furan,thiophene, pyrrole, oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole,isoxazole, imidazole, pyrazole, thiazole, triazole, thiadiazole,pyridine, pyrimidine, pyrazine and tetrazole. Examples of a five or sixmembered heteroaromatic ring containing 1 to 3 heteroatoms independentlyselected from O, S and N include furan, thiophene, pyrrole, oxazole,1,2,4-oxadiazole, 1,3,4-oxadiazole, isoxazole, imidazole, pyrazole,thiazole, triazole, thiadiazole, pyridine, pyrimidine and pyrazine.

Unless otherwise indicated, the term “C3 to 6 saturated or partiallyunsaturated cycloalkyl” referred to herein denotes a 3 to 6 memberednon-aromatic carbocyclic ring optionally incorporating one or moredouble bonds. Examples include cyclopropyl, cyclopentyl, cyclopentenyl,cyclohexyl and cyclohexenyl. The term “five- or six-membered saturatedor partially unsaturated cycloalkyl ring” is to be interpretedanalogously.

Unless otherwise indicated, the term “C4 to 7 saturated or partiallyunsaturated heterocyclic ring containing one or two heteroatomsindependently selected from O, S(O)_(p) and NR¹⁷ and optionally furtherincorporating a carbonyl group” referred to herein denotes a 4 to 7membered non-aromatic heterocyclic ring optionally incorporating one ormore double bonds and optionally incorporating a carbonyl group.Examples include tetrahydrofuran, thiolane 1,1-dioxide, tetrahydropyran,4-oxo-4H-pyran, pyrrolidine, pyrroline, imidazolidine, dihydro-oxazole,dihydropyrazole, 1,3-dioxolane, piperidine, piperazine, morpholine,perhydroazepine, pyrrolidone and piperidone. The term “five- orsix-membered saturated or partially unsaturated heterocyclic ringcontaining one heteroatom selected from O, S and NR¹³” is to beinterpreted analogously.

Examples of a “5 to 7 membered azacyclic ring optionally incorporatingone further heteroatom selected from O, S and NR¹⁶” include pyrrolidine,piperidine, morpholine, thiomorpholine and piperazine.

In the definition of L, “C1 to 6 alkyl; said alkyl optionallyincorporating a heteroatom selected from O, S and NR¹⁶” embraces astraight or branched chain arrangement of 1 to 6 carbon atoms in whichany two carbon atoms are optionally separated by O, S or NR¹⁶. Thedefinition thus includes, for example, methylene, ethylene, propylene,hexamethylene, ethylethylene, —CH₂CH₂O—CH₂—, —CH₂CH₂O—CH₂—CH₂—,—CH₂CH₂S— and —CH₂CH₂NR¹⁶—.

Examples of bicyclic ring systems in which the two rings are eitherfused together, or are bonded directly together or are separated by alinker group selected from O, S(O)_(q) or CH₂ include biphenyl,thienylphenyl, pyrazolylphenyl, phenoxyphenyl, phenylcyclopropyl,naphthyl, indanyl, quinolyl, tetrahydroquinolyl, benzofuranyl, indolyl,isoindolyl, indolinyl, benzofuranyl, benzothienyl, indazolyl,benzimidazolyl, benzthiazolyl, purinyl, isoquinolyl, chromanyl, indenyl,quinazolyl, quinoxalyl, chromanyl, isocromanyl, 3H-indolyl,1H-indazolyl, quinuclidyl, tetrahydronaphthyl, dihydrobenzofuranyl,morpholine-4-ylphenyl, 1,3-benzodioxolyl,1,1-dioxido-2,3-dihydro-1-benzothienyl, 2,3-dihydro-1,4-benzodioxinyl,1,3-benzodioxinyl, and 3,4-dihydro-isochromenyl.

In one embodiment, Y in formula (I) represents CR³. In anotherembodiment, Y represents N.

In one embodiment, R¹ in formula (I) represents C1 to 6 alkyl. Inanother embodiment, R¹ represents CH₃.

In one embodiment, R² in formula (I) represents optionally substitutedphenyl. In another embodiment, R² in formula (I) represents anoptionally substituted five- or six-membered heteroaromatic ringcontaining 1 to 4 heteroatoms selected independently from O, S and N. Inanother embodiment, R² in formula (I) represents an optionallysubstituted five- or six-membered heteroaromatic ring containing 1 to 3heteroatoms selected independently from O, S and N. In anotherembodiment, R² in formula (I) represents an optionally substitutedfive-membered heteroaromatic ring containing 2 or 3 heteroatoms selectedindependently from O, S and N. In another embodiment, R² in formula (I)represents optionally substituted furan, pyridine, pyrimidine, pyrrole,thiophene, thiazolo, isoxazole, oxadiazole or thiadiazole. In anotherembodiment, R² in formula (I) represents optionally substitutedisoxazole.

In one embodiment, R³ in formula (I) represents H.

In one embodiment, G¹ in formula (I) represents phenyl or pyridyl. Inanother embodiment, G¹ in formula (I) represents phenyl.

In one embodiment, R⁵ in formula (I) represents halogen, C1 to 6 alkyl,CN or C1 to 3 alkyl substituted by one or more F atoms. In anotherembodiment, R⁵ in formula (I) represents Cl, CH₃, CN or CF₃.

In one embodiment, n represents the integer 1.

In another embodiment, G¹ in formula (I) represents phenyl, R⁵represents CF₃ and n represents the integer 1.

In one embodiment, R⁴ represents H.

In one embodiment, L represents C1 to 6 alkyl. In another embodiment, Lrepresents —CH₂—. In another embodiment, L represents NR²⁹ and R²⁹represents H.

In one embodiment, G² represents an optionally substituted monocyclicring system selected from:

-   i) phenyl,-   ii) a 5 or 6 membered heteroaromatic ring containing one to three    heteroatoms independently selected from O, S and N,-   iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or-   iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring    containing one or two heteroatoms independently selected from O,    S(O)_(p) and NR¹⁷ and optionally further incorporating a carbonyl    group.

In another embodiment, G² represents optionally substituted phenyl. Inanother embodiment, G² represents phenyl substituted by OSO₂R³⁸,S(O)_(S)R²⁵, SO₂NR²⁶R²⁷, NR¹⁸R¹⁹ (wherein at least one of R¹⁸ and R¹⁹represents S(O)_(t)R³² or SO₂NR³³R³⁴) or C1 to 3 alkyl substituted bySO₂R³⁹. In another embodiment, G² represents phenyl substituted byS(O)_(s)R²⁵ and R²⁵ represents C1 to 6 alkyl or C3 to 6 cycloalkyl and srepresents the integer 2.

In another embodiment, G² represents an optionally substituted bicyclicring system in which each of the two rings is independently selectedfrom:

-   i) phenyl,-   ii) a 5 or 6 membered heteroaromatic ring containing one to three    heteroatoms independently selected from O, S and N,-   iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or-   iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring    containing one or two heteroatoms independently selected from O,    S(O)_(p) and NR¹⁷ and optionally further incorporating a carbonyl    group;    and the two rings are either fused together, or are bonded directly    together or are separated by a linker group selected from O,    S(O)_(q) or CH₂.

In one embodiment, Y in formula (I) represents CR³ and R³ represents H;R¹ represents C1 to 6 alkyl; R² represents an optionally substitutedfive- or six-membered heteroaromatic ring containing 1 to 3 heteroatomsselected independently from O, S and N; G¹ represents phenyl; R⁵represents halogen, C1 to 6 alkyl, CN or C1 to 3 alkyl substituted byone or more F atoms; R⁴ represents H; L represents C1 to 6 alkyl; and G²represents an optionally substituted monocyclic ring system selectedfrom:

-   i) phenyl,-   ii) a 5 or 6 membered heteroaromatic ring containing one to three    heteroatoms independently selected from O, S and N,-   iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or-   iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring    containing one or two heteroatoms independently selected from O,    S(O)_(p) and NR¹⁷ and optionally further incorporating a carbonyl    group.

In one embodiment, Y in formula (I) represents CR³ and R³ represents H;R¹ represents C1 to 6 alkyl; R² represents an optionally substitutedfive-membered heteroaromatic ring containing 1 to 3 heteroatoms selectedindependently from O, S and N; G¹ represents phenyl; R⁵ representshalogen, C1 to 6 alkyl, CN or C1 to 3 alkyl substituted by one or more Fatoms; R⁴ represents H; L represents C1 to 6 alkyl; and G² representsphenyl substituted by OSO₂R³⁸, S(O)_(s)R²⁵, SO₂NR²⁶R²⁷, NR¹⁸R¹⁹ (whereinat least one of R¹⁸ and R¹⁹ represents S(O)_(t)R³² or SO₂NR³³R³⁴) or C1to 3 alkyl substituted by SO₂R³⁹.

In one embodiment, Y in formula (I) represents CR³ and R³ represents H;R¹ represents methyl; R² represents an optionally substitutedfive-membered heteroaromatic ring containing 2 or 3 heteroatoms selectedindependently from O, S and N; G¹ represents phenyl; R⁵ represents Cl,CH₃, CN or CF₃; R⁴ represents H; L represents C1 to 6 alkyl; and G²represents phenyl substituted by OSO₂R³⁸, S(O)_(s)R²⁵, SO₂NR²⁶R²⁷,NR¹⁸R¹⁹ (wherein at least one of R¹⁸ and R¹⁹ represents S(O)_(t)R³² orSO₂NR³³R³⁴) or C1 to 3 alkyl substituted by SO₂R³⁹.

In one embodiment, Y in formula (I) represents CR³ and R³ represents H;R¹ represents methyl; R² represents an optionally substituted isoxazolering; G¹ represents phenyl; R⁵ represents Cl, CH₃, CN or CF₃; R⁴represents H; L represents C1 to 3 alkyl; and G² represents phenylsubstituted by OSO₂R³⁸, S(O)_(s)R²⁵, SO₂NR²⁶R²⁷, NR¹⁸R¹⁹ (wherein atleast one of R¹⁸ and R¹⁹ represents S(O)_(t)R³² or SO₂NR³³R³⁴) or C1 to3 alkyl substituted by SO₂R³⁹.

In one embodiment, Y in formula (I) represents CR³ and R³ represents H;R¹ represents methyl; R² represents an optionally substitutedfive-membered heteroaromatic ring containing 2 or 3 heteroatoms selectedindependently from O, S and N; G¹ represents phenyl; R⁵ represents Cl,CH₃, CN or CF₃; R⁴ represents H; L represents C1 to 6 alkyl; and G²represents phenyl substituted by S(O)_(s)R²⁵ and R²⁵ represents C1 to 6alkyl or C3 to 6 cycloalkyl and s represents the integer 2.

In one embodiment, Y in formula (I) represents CR³ and R³ represents H;R¹ represents methyl; R² represents an optionally substituted isoxazolering; G¹ represents phenyl; R⁵ represents Cl, CH₃, CN or CF₃; R⁴represents H; L represents C1 to 3 alkyl; and G² represents phenylsubstituted by S(O)_(s)R²⁵ and R²⁵ represents C1 to 6 alkyl or C3 to 6cycloalkyl and s represents the integer 2.

In one embodiment, Y in formula (I) represents CR³ or N; R¹ represents Hor C1 to 6 alkyl; R² represents phenyl or a five- or six-memberedheteroaromatic ring containing 1 to 4 heteroatoms independently selectedfrom O, S and N; said aromatic ring being optionally substituted by 1 to3 substituents selected independently from OH, halogen, C1 to 6 alkyl,C1 to 6 alkoxy, NCOR⁵⁰, COOR⁵¹, COR⁵², CONR⁵³R⁵⁴ and NR⁴⁷R⁴⁸; said alkylbeing optionally further substituted by OH, CN or CO₂R⁴⁹; R⁴⁷ and R⁴⁸independently represent H, C1 to 6 alkyl or C2 to 6 alkanoyl; R³represents H or F; G¹ represents phenyl or a five- or six-memberedheteroaromatic ring containing 1 to 3 heteroatoms independently selectedfrom O, S and N; R⁵ represents H, halogen, C1 to 6 alkyl, CN, C1 to 6alkoxy, NO₂, NR¹⁴R¹⁵, C1 to 3 alkyl substituted by one or more F atomsor C1 to 3 alkoxy substituted by one or more F atoms; R¹⁴ and R¹⁵independently represent H or C1 to 3 alkyl; said alkyl being optionallyfurther substituted by one or more F atoms; n represents an integer 1, 2or 3 and when n represents 2 or 3, each R⁵ group is selectedindependently; R⁴ represents H or C1 to 6 alkyl; said alkyl beingoptionally further substituted by OH or C1 to 6 alkoxy; or R⁴ and L arejoined together such that the group —NR⁴L represents a 5 to 7 memberedazacyclic ring optionally incorporating one further heteroatom selectedfrom O, S and NR¹⁶; L represents a bond, O, NR²⁹ or C1 to 6 alkyl; saidalkyl optionally incorporating a heteroatom selected from O, S and NR¹⁶;and said alkyl being optionally further substituted by OH or OMe; G²represents a monocyclic ring system selected from:

-   i) phenyl or phenoxy,-   ii) a 5 or 6 membered heteroaromatic ring containing one to three    heteroatoms independently selected from O, S and N,-   iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or-   iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring    containing one or two heteroatoms independently selected from O,    S(O)_(p) and NR¹⁷ and optionally further incorporating a carbonyl    group; or

G² represents a bicyclic ring system in which each of the two rings isindependently selected from:

-   i) phenyl,-   ii) a 5 or 6 membered heteroaromatic ring containing one to three    heteroatoms independently selected from O, S and N,-   iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or-   iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring    containing one or two heteroatoms independently selected from O,    S(O)_(p) and NR¹⁷ and optionally further incorporating a carbonyl    group;    and the two rings are either fused together, or are bonded directly    together or are separated by a linker group selected from O,    S(O)_(q) or CH₂; said monocyclic or bicyclic ring system being    optionally further substituted by one to three substituents    independently selected from CN, OH, C1 to 6 alkyl, C1 to 6 alkoxy,    halogen, NR¹⁸R¹⁹, NO₂, OSO₂R³⁸, CO₂R², C(═NH)NH₂, C(O)NR²¹R²²,    C(S)NR²³R²⁴, SC(═NH)NH₂, NR³¹C(═NH)NH₂, S(O)_(s)R²⁵, SO₂NR²⁶R²⁷, C1    to 3 alkoxy substituted by one or more F atoms and C1 to 3 alkyl    substituted by SO₂R³⁹ or by one or more F atoms; or when L does not    represent an bond, G² may also represent H; p, q, s and t    independently represent an integer 0, 1 or 2; R¹⁸ and R¹⁹,    independently represent H, C1 to 6 alkyl, formyl, C2 to 6 alkanoyl,    S(O)_(t)R³² or SO₂NR³³R³⁴; said alkyl group being optionally further    substituted by halogen, CN, C1 to 4 alkoxy or CONR⁴¹R⁴²; R²⁵    represents H, C1 to 6 alkyl or C3 to 6 cycloalkyl; said alkyl group    being optionally further substituted by one or more substituents    selected independently from OH, CN, CONR³⁵R³⁶, CO₂R³⁷, OCOR⁴⁰, C3 to    6 cycloalkyl, a C4 to 7 saturated heterocyclic ring containing one    or two heteroatoms independently selected from O, S(O)_(p) and NR⁴³    and phenyl or a 5 or 6 membered heteroaromatic ring containing one    to three heteroatoms independently selected from O, S and N; said    aromatic ring being optionally further substituted by one or more    substituents selected independently from halogen, CN, C1 to 4 alkyl,    C1 to 4 alkoxy, OH, CONR⁴⁴R⁴⁵, CO₂R⁴⁶, S(O)_(s)R⁵⁵ and NHCOCH₃; R³²    represents H, C1 to 6 alkyl or C3 to 6 cycloalkyl; and R¹⁶, R¹⁷,    R²⁰, R²¹, R²², R²³, R²⁴, R²⁶, R²⁷, R²⁹, R³¹, R³³, R³⁴, R³⁵, R³⁶,    R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁹, R⁵⁰, R⁵¹,    R⁵², R⁵³, R⁵⁴ and R⁵⁵ independently represent H or C1 to 6 alkyl.

In another aspect, the invention specifically provides any compound asdescribed in the Examples herein, or the free base thereof or apharmaceutically acceptable salt thereof. Particular compounds include:

-   6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   5-[4-(hydroxymethyl)phenyl]-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   5-furan-3-yl-6-methyl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   6′-methoxy-2-methyl-N-[4-(methylsulfonyl)benzyl]-6-oxo-1-[3-(trifluoromethyl)phenyl]-1,6-dihydro-3,3′-bipyridine-5-carboxamide;-   5-(2-methoxypyrimidin-5-yl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   5-[4-(acetylamino)phenyl]-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-2-oxo-5-(1H-pyrrol-3-yl)-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   5-furan-2-yl-6-methyl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   6-methyl-2-oxo-5-thiophen-3-yl-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   6-methyl-2-oxo-5-thiophen-2-yl-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   5-(3,5-dimethyl-isoxazol-4-yl)-6-methyl-2-oxo-1-(3-trifluoromethylphenyl)-1,1-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   5-(2,4-dimethoxy-pyrimidin-5-yl)-6-methyl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   5-(2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   6-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   6-methyl-2-oxo-5-(5-propyl-[1,3,4]oxadiazol-2-yl)-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   {5-[5-(4-methanesulfonyl-benzylcarbamoyl)-2-methyl-6-oxo-1-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridin-3-yl]-[1,3,4]oxadiazol-2-yl}-acetic    acid ethyl ester;-   5-(5-cyanomethyl-[1,3,4]oxadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   5-(5-amino-[1,3,4]oxadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   5-(5-amino-[1,3,4]thiadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   5-(5-ethylamino-[1,3,4]oxadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   5-(5-N,N-dimethylamino-[1,3,4]oxadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-pyrazin-2-yl-1-[3-(trifluoro-methyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-5-oxazol-2-yl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   6-methyl-5-(1-methyl-1H-imidazol-2-yl)-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   6-methyl-2-oxo-5-(1H-pyrazol-4-yl)-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-pyrimidin-2-yl-1-[3-(trifluoro-methyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-1-(trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   6-methyl-5-(3-methylisoxazol-4-yl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1,3-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide;-   6-methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   6-methyl-5-(3-methylisoxazol-5-yl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   5-(3,5-dimethylisoxazol-4-yl)-N-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   5-(3,5-dimethylisoxazol-4-yl)-N-[4-(ethylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   N-[4-(cyclopropylsulfonyl)benzyl]-5-(3,5-dimethylisoxazol-4-yl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   1-(3-cyanophenyl)-5-(3,5-dimethylisoxazol-4-yl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydropyridine-3-carboxamide;-   1-(3-chlorophenyl)-5-(3,5-dimethyl-isoxazol-4-yl)-6-methyl-2-oxo-1,2-dihydro-pyridine-3-carboxylic    acid 4-Methanesulfonyl-benzylamide;-   5-(3,5-dimethyl-isoxazol-4-yl)-6-methyl-2-oxo-1-m-tolyl-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   5-(5-isopropyl-[1,3,4]oxadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   6-methyl-5-[1,3,4]oxadiazol-2-yl)-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   5-(5-hydroxy-[1,3,4]oxadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   6-methyl-5-(5-methyl-4H-[1,2,4]triazol-3-yl)-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methylsulfonyl-benzylamide;-   5-(4,5-dimethyl-4H-[1,2,4]triazol-3-yl)-6-methyl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   5-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   N-[4-(isopropylsulfonyl)benzyl]-6-methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   N-[4-(ethylsulfonyl)benzyl]-6-methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   N-[4-(cyclopropylsulfonyl)benzyl]-6-methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-5-[1,3,4]oxadiazol-2-yl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-(propane-2-sulfonyl)-benzylamide;-   6-methyl-5-[1,3,4]oxadiazol-2-yl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-cyclopropanesulfonyl-benzylamide;-   6-methyl-5-(2-methyl-1,3-oxazol-4-yl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-N-[4-(methylsulfonyl)benzyl]-5-(1,3-oxazol-4-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   5-(2-amino-thiazol-4-yl)-6-methyl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-j-carboxylic    acid 4-methanesulfonyl-benzylamide;-   5-(2,5-dimethyl-1,3-oxazol-4-yl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1,3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-5-(5-methyl-1,3-oxazol-4-A-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   5-(2-amino-5-methyl-thiazol-4-yl)-6-methyl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   5-(2-hydroxymethyl-5-methyl-thiazol-4-yl)-6-methyl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   6-methyl-5-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   6-methyl-5-[1,2,4]oxadiazol-3-yl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   6-methyl-2-oxo-5-(1H-tetrazol-5-yl)-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   6-methyl-5-(4-methyl-oxazol-2-yl)-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   5-(4,5-dimethyl-oxazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid 4-methanesulfonyl-benzylamide;-   N-(cyclohexylmethyl)-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-N-(2-morpholin-4-ylethyl)-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-2-oxo-5-phenyl-N-1H-1,2,4-triazol-3-yl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   N-[2-(1H-indol-3-yl)ethyl]-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-2-oxo-5-phenyl-N-(1-phenylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-2-oxo-5-phenyl-N-(2-phenylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-2-oxo-5-phenyl-N-[(2R)-2-phenylcyclopropyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   N-(2,3-dihydro-1H-inden-2-yl)-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   N-[(1-ethylpyrrolidin-2-yl)methyl]-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-N-(1-naphthylmethyl)-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   N-(1,3-benzodioxol-5-ylmethyl)-6-methyl-2-oxo-5-Phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   N-(2-chloro-4-fluorobenzyl)-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-2-oxo-5-phenyl-N-(2-thienylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   N-(2-cyclohex-1-en-1-ylethyl)-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-2-oxo-N-(4-phenoxybenzyl)-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   N-[(2,5-dimethyl-3-furyl)methyl]-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide;-   N-{2-[4-(aminosulfonyl)phenyl]ethyl}-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-2-oxo-5-phenyl-N-[4-(1H-pyrazol-1-yl)benzyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-2-oxo-N-phenoxy-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydro-pyridine-3-carboxamide;-   N-[(6-fluoro-4H-1,3-benzodioxin-8-yl)methyl]-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-2-oxo-5-phenyl-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-2-oxo-5-phenyl-N-[3-(1H-pyrazol-1-yl)propyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-oxo-5-phenyl-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-2-oxo-5-phenyl-N-[(1-phenyl-1H-pyrazol-4-yl)methyl]-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide;-   N-[(5-methoxy-4-oxo-4H-pyran-2-yl)methyl]-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   N-(3-azepan-1-ylpropyl)-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   N-(4-cyanobenzyl)-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-2-oxo-N-[3-(5-oxo-4,5-dihydro-1H-pyrazol-4-yl)propyl]-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   6-methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid (3-methyl-isoxazol-5-ylmethyl)-amide;-   6-methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid (5-methanesulfonylmethyl-[1,2,4]oxadiazol-3-ylmethyl)-amide;-   6-methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylic    acid ([1,2,4]oxadiazol-3-ylmethyl)-amide;-   6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;-   5-(3,5-dimethylisoxazol-4-yl)-6-methyl-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide;    acceptable salts thereof.

The present invention includes compounds of formula (I) in the form ofsalts, in particular acid addition salts. Suitable salts include thoseformed with both organic and inorganic acids. Such acid addition saltswill normally be pharmaceutically acceptable although salts ofnon-pharmaceutically acceptable acids may be of utility in thepreparation and purification of the compound in question. Thus,preferred salts include those formed from hydrochloric, hydrobromic,sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic,succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.

In a further aspect the invention provides a process for the preparationof a compound of formula (I) which comprises:

a) reacting a compound of formula (II)

wherein R¹, R⁴, R⁵, Y, G¹, G², L and n are as defined in formula (I) andHal represents a halogen atom, preferably bromo or iodo;with a nucleophile R²-M wherein R² is as defined in formula (I) and Mrepresents an organo-tin or organo boronic acid group; orb) when R² represents a 1,3,4-oxadiazol-2-yl or a 1,3,4-thiadiazol-2-ylring, reacting a compound of formula (III)

wherein R¹, R⁴, R⁵, Y, G¹, G², L and n are as defined in formula (I), Zrepresents O or S and X represents C1 to 6 alkyl or NR⁴⁷R⁴⁸ and R⁴⁷ andR⁴⁸ are as defined in formula (I); with a suitable dehydrating agentsuch as phosphoryl chloride or trimethylsilyl polyphosphate; orc) reacting a compound of formula (XV)

wherein R¹, R², R⁵, n, G¹, and Y are as defined in formula (I) and L¹represents a leaving group,with a compound of formula (IX) or a salt thereof

wherein R⁴, G² and L are as defined in formula (I);and where desired or necessary converting the resultant compound offormula (I), or another salt thereof, into a pharmaceutically acceptablesalt thereof; or converting one compound of formula (I) into anothercompound of formula (I); and where desired converting the resultantcompound of formula (I) into an optical isomer thereof.

In process (a), the reaction is carried out at a suitable temperature,generally between 50° C. and 150° C. in a suitable solvent such astoluene in the presence of a transition metal catalyst such aspalladium. Optionally, the reaction may be carried out in the presenceof a base such as potassium carbonate.

In process (b), the reaction is carried out at a suitable temperature,generally between 20° C. and 100° C. in a suitable solvent such asdichloromethane, if necessary, using a sealed vial.

The man skilled in the art will readily appreciate that compounds offormula (I) wherein R² represents a five-membered heteroaromatic ringother than a 1,3,4-oxadiazol-2-yl or a 1,3,4-thiadiazol-2-yl ring mayalso be prepared by processes in which the final step is the ringclosure of the five-membered heteroaromatic ring. Specific examples ofsuch processes are described in the Examples section of thisspecification. Such processes form another aspect of the presentinvention.

In process (c), the reaction is carried out at a suitable temperature,generally between 0° C. and the boiling point of the solvent, in asuitable solvent such as dichloromethane or N-methylpyrrolidinone. Theprocess is optionally carried out in the presence of a base and/or acoupling reagent such as HATU, HOAT, HOBT or DIEA. Suitable leavinggroups L¹ include OH and halogen.

Compounds of formula (III) may be prepared by reacting a compound offormula (IV)

wherein R¹, R⁴, R⁵, Y, G¹, G², L and n are as defined in formula (I);with a compound of the general formula (V)

wherein X is defined in formula (III). This reaction may be carried outat a suitable temperature, generally between 0° C. and 50° C. in asuitable solvent such as 1,4-dioxane.

Compounds of formula (IV) may be prepared by reacting a compound offormula (VI)

wherein R¹, R⁴, R⁵, Y, G¹, G², L and n are as defined in formula (I) andR represents C1 to 6 alkyl;with an aqueous base such as sodium hydroxide, followed by subsequenttreatment of the product with a chlorinating agent such as thionylchloride. This process may be carried out at a suitable temperature;generally between 10° C. and 50° C. in a suitable solvent such astetrahydrofuran or dichloromethane.

Compounds of formula (VI) may be prepared by reacting a compound offormula (II) with carbon monoxide in the presence of an alcohol such asmethanol or ethanol and in the presence of a suitable transition metalcatalyst. This process may be carried out at a suitable temperature,generally between 50° C. and 150° C. in a suitable solvent such asmethanol or ethanol in a carbon monoxide atmosphere at elevatedpressure, generally between 2 and 10 atmospheres. The reaction isperformed in the presence of a transition metal catalyst such aspalladium.

Compounds of formula (II) may be prepared by reacting a compound offormula (VII)

wherein R¹, R⁴, R⁵, Y, G¹, G², L and n are as defined in formula (I),with a halogenating agent, such as N-iodosuccinimide. This process iscarried out at a suitable temperature, generally between 0° C. and 50°C. in a suitable solvent such as acetonitrile in the presence of an acidsuch as trifluoromethanesulfonic acid.

Compounds of formula (VII) can be prepared by reacting a compound offormula (VIII)

wherein R¹, R⁵, Y, G¹ and n are as defined in formula (I) and L¹represents a leaving group, with an amine of formula (IX) or a saltthereof

wherein R⁴, G² and L are as defined in formula (I). The process iscarried out at a suitable temperature, generally between 0° C. and theboiling point of the solvent, in a suitable solvent such asdichloromethane or N-methylpyrrolidinone. The process is optionallycarried out in the presence of a base and/or a coupling reagent such asHATU, HOAT, HOBT or DIEA. Suitable leaving groups L¹ include OH andhalogen.

Compounds of formula (VIII) wherein Y is CR³, L¹ is OH and R³ ishydrogen can be prepared by condensing a compound of formula (X)

wherein R¹ is as defined in formula (I); with a compound of formula (XI)

wherein G¹, R⁵ and n are as defined in formula (I), in the presence of asuitable base, such as sodium methoxide, in a suitable solvent, such asethanol, followed by hydrolysis using a suitable base such as sodiumhydroxide.

In general, compounds of formulae (X) and (XI) are either known or maybe prepared using methods that will be readily apparent to the manskilled in the art. For example, compounds of formula (X) can beprepared according to the methods of S. M. Brombridge et al., SyntheticCommunications, 1993, 23, 487-494. And compounds of formula (XI) can beprepared according to the methods of Igor V. Ukrainets et al.,Tetrahedron, 1994, 50, 10331-10338.

Compounds of formula (VIII) wherein Y is CR³, L¹ is OH and R¹ ishydrogen can be prepared by reacting a compound of formula (XII).

wherein G¹, R⁵ and n are as defined in formula (I), with a compound offormula (XIII)

wherein R³ is as defined in formula (I), at a suitable temperature, suchas 160° C., followed by base promoted cyclisation and acid hydrolysis.Compounds of formula (XIII) can be prepared according to U.S. Pat. No.3,838,155.

Compounds of formula (VIII) wherein Y is CR³, L¹ is OH, R¹ is methyl andR³ is hydrogen can be prepared by condensing a compound of formula(XIV).

wherein G¹, R⁵ and n are as defined in formula (I), with4-methoxy-3-buten-2-one in the presence of a suitable base, such as1,4-diazabicyclo[2.2.2]octane, at a suitable temperature in a suitablesolvent such as diethyleneglycol monomethyl ether, followed by acidhydrolysis.

Salts of compounds of formula (I) may be formed by reacting the freebase or a salt, enantiomer, tautomer or protected derivative thereof,with one or more equivalents of the appropriate acid. The reaction maybe carried out in a solvent or medium in which the salt is insoluble, orin a solvent in which the salt is soluble followed by subsequent removalof the solvent in vacuo or by freeze drying. Suitable solvents include,for example, water, dioxane, ethanol, 2-propanol, tetrahydrofuran ordiethyl ether, or mixtures thereof. The reaction may be a metatheticalprocess or it may be carried out on an ion exchange resin.

Compounds of formula (I) and intermediate compounds thereto may beprepared as such or in protected form. The protection and deprotectionof functional groups is, for example, described in ‘Protective Groups inOrganic Chemistry’, edited by J. W. F. McOmie, Plenum Press (1973), and‘Protective Groups in Organic Synthesis’, 3rd edition, T. W. Greene & P.G. M. Wuts, Wiley-Interscience (1999).

The compounds of the invention and intermediates may be isolated fromtheir reaction mixtures, and if necessary further purified, by usingstandard techniques.

The compounds of formula (I) may exist in enantiomeric ordiastereoisomeric forms or mixtures thereof, all of which are includedwithin the scope of the invention. The various optical isomers may beisolated by separation of a racemic mixture of the compounds usingconventional techniques, for example, fractional crystallisation orHPLC. Alternatively, the individual enantiomers may be made by reactionof the appropriate optically active starting materials under reactionconditions that will not cause racemisation.

Intermediate compounds may also exist in enantiomeric forms and may beused as purified enantiomers, diastereomers, racemates or mixturesthereof.

According to a further aspect of the invention we provide a compound offormula (I) or a pharmaceutically acceptable salt thereof, for use as amedicament.

The compounds of formula (I), and their pharmaceutically acceptablesalts, are useful because they possess pharmacological activity inanimals. The compounds of formula (I) have activity as pharmaceuticals,in particular as modulators of human neutrophil elastase and homologousserine proteases such as proteinase 3 and pancreatic elastase, and assuch are predicted to be useful in therapy. The compounds of formula (I)are particularly useful as inhibitors of human neutrophil elastase. Theymay thus be used in the treatment or prophylaxis of inflammatorydiseases and conditions.

Examples of these conditions are: adult respiratory distress syndrome(ARDS), cystic fibrosis, pulmonary emphysema, chronic obstructivepulmonary disease (COPD) and ischaemic-reperfusion injury. The compoundsof this invention may also be useful in the modulation of endogenousand/or exogenous biological irritants which cause and/or propagateatherosclerosis, diabetes, myocardial infarction; hepatic disordersincluding but not limited to cirrhosis, systemic lupus erythematous,inflammatory disease of lymphoid origin, including but not limited to Tlymphocytes, B lymphocytes, thymocytes; autoimmune diseases, bonemarrow; inflammation of the joint (especially rheumatoid arthritis,osteoarthritis and gout); inflammation of the gastro-intestinal tract(especially inflammatory bowel disease, ulcerative colitis, pancreatitisand gastritis); inflammation of the skin (especially psoriasis, eczema,dermatitis); in tumour metastasis or invasion; in disease associatedwith uncontrolled degradation of the extracellular matrix such asosteoarthritis; in bone resorptive disease (such as osteoporosis andPaget's disease); diseases associated with aberrant angiogenesis; theenhanced collagen remodelling associated with diabetes, periodontaldisease (such as gingivitis), corneal ulceration, ulceration of theskin, post-operative conditions (such as colonic anastomosis) and dermalwound healing; demyelinating diseases of the central and peripheralnervous systems (such as multiple sclerosis); age related illness suchas dementia, inflammatory diseases of cardiovascular origins;granulomatous diseases; renal diseases including but not limited tonephritis and polyarteritis; cancer; pulmonary hypertension, ingestedpoisons, skin contacts, stings, bites; asthma; rhinitis; HIV diseaseprogression; for minimising the effects of organ rejection in organtransplantation including but not limited to human organs; andreplacement therapy of proteinase inhibitors.

Thus, another aspect of the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment or prophylaxis of diseasesor conditions in which inhibition of neutrophil elastase activity isbeneficial; and a method of treating, or reducing the risk of, diseasesor conditions in which inhibition of neutrophil elastase activity isbeneficial which comprises administering to a person suffering from orat risk of, said disease or condition, a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

In another aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment or prophylaxis ofinflammatory diseases or conditions; and a method of treating, orreducing the risk of, inflammatory diseases or conditions whichcomprises administering to a person suffering from or at risk of, saiddisease or condition, a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof.

In particular, the compounds of this invention may be used in thetreatment of adult respiratory distress syndrome (ARDS), cysticfibrosis, pulmonary emphysema, chronic obstructive pulmonary disease(COPD), pulmonary hypertension, asthma, rhinitis, ischemia-reperfusioninjury, rheumatoid arthritis, osteoarthritis, cancer, atherosclerosisand gastric mucosal injury.

Prophylaxis is expected to be particularly relevant to the treatment ofpersons who have suffered a previous episode of, or are otherwiseconsidered to be at increased risk of, the disease or condition inquestion. Persons at risk of developing a particular disease orcondition generally include those having a family history of the diseaseor condition, or those who have been identified by genetic testing orscreening to be particularly susceptible to developing the disease orcondition.

For the above mentioned therapeutic indications, the dose of thecompound to be administered will depend on the compound employed, thedisease being treated, the mode of administration, the age, weight andsex of the patient. Such factors may be determined by the attendingphysician. However, in general, satisfactory results are obtained whenthe compounds are administered to a human at a daily dosage of between0.1 mg/kg to 100 mg/kg (measured as the active ingredient).

The compounds of formula (I) may be used on their own, or in the form ofappropriate pharmaceutical formulations comprising the compound of theinvention in combination with a pharmaceutically acceptable diluent,adjuvant or carrier. Particularly preferred are compositions notcontaining material capable of causing an adverse reaction, for example,an allergic reaction. Conventional procedures for the selection andpreparation of suitable pharmaceutical formulations are described in,for example, “Pharmaceuticals—The Science of Dosage Form Designs”, M. E.Aulton, Churchill Livingstone, 1988.

According to the invention, there is provided a pharmaceuticalformulation comprising preferably less than 95% by weight and morepreferably less than 50% by weight of a compound of formula (I) inadmixture with a pharmaceutically acceptable diluent or carrier.

We also provide a method of preparation of such pharmaceuticalformulations that comprises mixing the ingredients.

The compounds may be administered topically, for example, to the lungsand/or the airways, in the form of solutions, suspensions, HFA aerosolsor dry powder formulations, for example, formulations in the inhalerdevice known as the Turbuhaler®; or systemically, for example, by oraladministration in the form of tablets, pills, capsules, syrups, powdersor granules; or by parenteral administration, for example, in the formof sterile parenteral solutions or suspensions; or by rectaladministration, for example, in the form of suppositories.

Dry powder formulations and pressurized HFA aerosols of the compounds ofthe invention may be administered by oral or nasal inhalation. Forinhalation, the compound is desirably finely divided. The finely dividedcompound preferably has a mass median diameter of less than 10 μm, andmay be suspended in a propellant mixture with the assistance of adispersant, such as a C₈-C₂₀ fatty acid or salt thereof, (for example,oleic acid), a bile salt, a phospholipid, an alkyl saccharide, aperfluorinated or polyethoxylated surfactant, or other pharmaceuticallyacceptable dispersant.

The compounds of the invention may also be administered by means of adry powder inhaler. The inhaler may be a single or a multi dose inhaler,and may be a breath actuated dry powder inhaler.

One possibility is to mix the finely divided compound with a carriersubstance, for example, a mono-, di- or polysaccharide, a sugar alcohol,or an other polyol. Suitable carriers are sugars, for example, lactose,glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose,mannitol; and starch. Alternatively the finely divided compound may becoated by another substance. The powder mixture may also be dispensedinto hard gelatine capsules, each containing the desired dose of theactive compound.

Another possibility is to process the finely divided powder into sphereswhich break up during the inhalation procedure. This spheronized powdermay be filled into the drug reservoir of a multidose inhaler, forexample, that known as the Turbuhaler® in which a dosing unit meters thedesired dose which is then inhaled by the patient. With this system theactive compound, with or without a carrier substance, is delivered tothe patient.

For oral administration the active compound may be admixed with anadjuvant or a carrier, for example, lactose, saccharose, sorbitol,mannitol; a starch, for example, potato starch, corn starch oramylopectin; a cellulose derivative; a binder, for example, gelatine orpolyvinylpyrrolidone; and/or a lubricant, for example, magnesiumstearate, calcium stearate, polyethylene glycol, a wax, paraffin, andthe like, and then compressed into tablets. If coated tablets arerequired, the cores, prepared as described above, may be coated with aconcentrated sugar solution which may contain, for example, gum arabic,gelatine, talcum, titanium dioxide, and the like. Alternatively, thetablet may be coated with a suitable polymer dissolved in a readilyvolatile organic solvent.

For the preparation of soft gelatine capsules, the compound may beadmixed with, for example, a vegetable oil or polyethylene glycol. Hardgelatine capsules may contain granules of the compound using either theabove mentioned excipients for tablets. Also liquid or semisolidformulations of the drug may be filled into hard gelatine capsules.

Liquid preparations for oral application may be in the form of syrups orsuspensions, for example, solutions containing the compound, the balancebeing sugar and a mixture of ethanol, water, glycerol and propyleneglycol. Optionally such liquid preparations may contain colouringagents, flavouring agents, saccharine and/or carboxymethylcellulose as athickening agent or other excipients known to those skilled in art.

The compounds of the invention may also be administered in conjunctionwith other compounds used for the treatment of the above conditions.

The following Examples are intended to illustrate, but in no way limitthe scope of the invention.

General Methods

¹H NMR and ¹³C NMR spectra were recorded on a Varian Inova 400 MHz or aVarian Mercury-VX 300 MHz instrument. The central peaks of chloroform-d(δ_(H) 7.27 ppm), dimethylsulfoxide-d₆ (δ_(H) 2.50 ppm), acetonitrile-d₃(δ_(H) 1.95 ppm) or methanol-d₄ (δ_(H) 3.31 ppm) were used as internalreferences. Column chromatography was carried out using silica gel(0.040-0.063 mm, Merck). Unless stated otherwise, starting materialswere commercially available. All solvents and commercial reagents wereof laboratory grade and were used as received.

The following abbreviations are used:

-   HBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate;-   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate;-   HOBT 1-Hydroxybenzotriazole;-   HOAT 1-Hydroxy-7-azabenzotriazole;-   DIEA N,N-Diisopropylethylamine;-   NMP 1-N-Methyl-2-pyrrolidinone;-   DME 1,2-Dimethoxyethane;-   THF Tetrahydrofuran;-   TFA Trifluoroacetic acid;-   DMF N,N-Dimethylformamide;-   DCM Dichloromethane.

The following method was used for LC/MS analysis:

Instrument Agilent 1100; Column Waters Symmetry 2.1×30 mm; Mass APCI;Flow rate 0.7 mL/min; Wavelength 254 nm; Solvent A: water+0.1% TFA;Solvent B: acetonitrile+0.1% TFA; Gradient 15-95%/B 8 min, 95% B 1 min.

Analytical chromatography was run on a Symmetry C₁₈-column, 2.1×30 mmwith 3.5 μm particle size, with acetonitrile/water/0.1% trifluoroaceticacid as mobile phase in a gradient from 5% to 95% acetonitrile over 8minutes at a flow of 0.7 ml/min.

Example 16-Methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidea) Ethyl 3-oxo-3-{[3-(trifluoromethyl)phenyl}amino]propanoate

To an ice-cooled solution of 3-(trifluoromethyl)aniline (64.5 g, 0.40mol) and triethylamine (60 ml) in acetone (700 ml) was added dropwise,ethyl 3-chloro-3-oxopropanoate (63.6 g, 0.42 mol) in acetone (50 ml).After the addition (approx. 30 minutes) stirring was continued at roomtemperature overnight. The solvents were removed and water (1200 ml) wasadded. The resulting precipitate was filtered off, thoroughly washedtwice with water and then dried to afford the title compound as yellowpowder (109 g, 99%).

¹H NMR (CDCl₃): δ 9.52 (1H, s); 7.87 (1H, s); 7.78 (1H, d); 7.46 (1H,t); 7.39 (1H, d); 4.29 (2H, q); 3.50 (2H, s); 1.35 (3H, t).

APCI-MS m/z: 276.1 [MH⁺].

b)6-Methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid

To a solution of ethyl3-oxo-3-{[3-(trifluoromethyl)phenyl]amino}propanoate (19.2 g, 70 mmol)and sodium methoxide (7.6 g, 140 mmol) in EtOH (250 ml) was added4-methoxybut-3-en-2-one (90%) (7.72 g, 77 mmol). After the addition, thereaction mixture was refluxed for 2 h and then cooled. Water (50 ml) and2M NaOH were added and the mixture was stirred at room temperatureovernight. The organic solvents were removed and the reaction mixturewas extracted (washed) with EtOAc. The water phases were acidified withhydrochloric acid to pH 3-4, an orange coloured precipitate appeared andwas filtered off, washed with water and dried. Recrystallisation twicefrom heptane/EtOAc (4:1) afforded the title compound (12 g, 58%) as awhite powder.

¹H NMR (CDCl₃): δ 13.68 (1H, s); 8.54 (1H, d); 7.86 (1H, d); 7.79 (1H,t); 7.55 (1H, brs); 7.48 (1H, d); 6.58 (1H, d); 2.16 (3H, s).

APCI-MS m/z: 298.1 [MH⁺].

c)6-Methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

A mixture of6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid (7.43 g, 25 mmol), HATU (10.5 g, 27.5 mmol), HOAT (3.75 g, 27.5mmol) and DIEA (14.2 ml, 82.5 mmol) in NMP (65 ml) was reacted for 1 h,then 4-methylsulphonylbenzyl amine hydrochloride (5.8 g, 26 mmol) wasadded. After 1 h, the reaction mixture was slowly poured into stirredice water (1 L). A powder was formed, and the water mixture wasacidified to pH 3 with citric acid (0.5 M), and stirring was continuedfor 1 h. The precipitate was filtered off, washed with water and driedin vacuum overnight. Recrystallisation from EtOAc gave 8.1 g (70%).

¹H NMR (CDCl₃): δ 10.00 (1H, brt); 8.60 (1H, d); 7.88 (2H, d); 7.83 (1H,d); 7.76 (1H, t); 7.53 (3H, m); 7.46 (1H, d); 6.49 (1H, d); 4.68 (2H,m); 3.03 (3H, s); 2.10 (3H, s).

APCI-MS m/z: 465.1 [MH⁺].

d)5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

To a solution of6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(200 mg, 0.43 mmol) in MeCN (1.5 ml) at room temperature and under argonwas added trifluoromethanesulfonic acid (1 ml) followed byN-iodosuccinimide (97 mg, 0.43 mmol). After 45 min, the reaction mixturewas diluted with DCM, washed with aqueous NaHCO₃, with aqueous NaS₂O₄and water, dried (Na₂SO₄), and evaporated to give the title compound(200 mg).

¹H NMR (CDCl₃): δ 9.85 (1H, brt); 8.90 (1H, d); 7.88 (2H, d); 7.76 (2H,m); 7.50 (2H, d); 7.48 (1H, s); 7.40 (1H, d); 4.65 (2H, m); 3.03 (3H,s); 2.32 (3H, s).

APCI-MS m/z: 591.0 [MH⁺].

e)6-Methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

A mixture of phenylboronic acid (25 mg, 0.20 mmol), 1,1′bis(diphenylphosphino)ferrocenedichloropalladium(II) (4 mg, 0.005 mmol),5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(100 mg 0.17 mmol), toluene (1 ml), ethanol (99%, 0.25 ml) and Na₂CO₃(2M, 0.25 ml) was stirred at 80° C. overnight, concentrated and theresidue was purified by flash chromatography to give the title compound(70 mg, 76%).

¹H NMR (CDCl₃): δ 10.04 (1H, brt); 8.64 (1H, s); 7.88 (2H, d); 7.82 (1H,d); 7.76 (1H, t); 7.58 (1H, s); 7.54-7.39 (6H, m); 7.31 (2H, d); 4.69(2H, m); 3.02 (3H, s); 2.03 (3H, s).

APCI-MS m/z: 541 [MH⁺].

Example 25-Furan-3-yl-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-Pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

A mixture of5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(Example 1 (d), 0.0413 g, 0.07 mmol), furan-3-boronic acid (0.009 g,0.08 mmol), Pd(PPh₃)₄ (0.004 g, 3.46 nmol), DME (2 ml) and Na₂CO₃ (2 ml,2M) was vigorously stirred under nitrogen in a sealed vial at 80° C. for2 h. Another portion of furan-3-boronic acid (0.005 g) and Pd(PPh₃)₄(0.004 g) was added and the reaction was allowed to go for another hour.The mixture was allowed to cool, and was then partitioned between EtOAcand water. The organic phase was collected and the aqueous phase wasextracted with another portion of EtOAc (10 ml). The combined organicphases were washed with water, brine, and dried over Na₂SO₄. Filtrationand evaporation gave a crude oil which was purified on silica(heptane:EtOAc 2:1 to 1:1 to 1:2), which after evaporation of purefractions gave 0.023 g (62%) of the title compound as a white solid.

¹H NMR (DMSO-d₆): δ 9.94 (1H, t, J 6.0 Hz); 8.36 (1H, s); 7.96-7.73 (7H,m); 7.54 (2H, d, J 8.14 Hz); 7.46 (1H, d, J 7.4 Hz); 6.73 (1H, s); 4.59(2H, d, J 6.13 Hz); 3.17 (3H, s); 2.06 (3H, s).

APCI-MS m/z: 531.3 [MH⁺].

Using the general method of Example 1, the compounds of Examples 3 to 6were prepared:

Example 35-[4-(Hydroxymethyl)phenyl]-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 10.04 (1H, brs); 8.64 (1H, brs); 7.88-7.77 (4H, m);7.58-7.47 (6H, m); 7.32 (2H, brs); 4.78 (2H, s) 4.70 (2H, brs); 3.02(3H, s); 2.03 (3H, s).

APCI-MS m/z: 571 [MH⁺].

Example 46′-Methoxy-2-methyl-N-[4-(methylsulfonyl)benzyl]-6-oxo-1-[3-(trifluoromethyl)phenyl]-1,6-dihydro-3,3′-bipyridine-5-carboxamide

¹H NMR (CDCl₃): δ 10.00 (1H, t); 8.58 (1H, s); 8.12 (1H, d); 7.89-7.74(4H, m); 7.58-7.49 (5H, m); 6.85 (1H, d); 4.69 (2H, m); 4.00 (3H, s);3.02 (3H, s); 2.02 (3H, s).

APCI-MS m/z: 572[MH⁺].

Example 55-(2-Methoxypyrimidin-5-yl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.93 (1H, brt); 8.56 (1H, s); 8.51 (2H, s); 7.89-7.75(4H, m); 7.57-7.48 (4H, m); 4.69 (2H., m); 4.09 (3H, s); 3.02 (3H, s);2.02 (3H, s).

APCI-MS m/z: 573[MH⁺].

Example 65-[4-(Acetylamino)phenyl]-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ10.05 (1H, brt); 8.61 (1H, s); 7.89-7.73 (4H, m);7.61-7.49 (6H, m); 7.39 (1H, s); 7.24 (1H, s) 4.69 (2H, m); 3.02 (3H,s); 2.21 (3H, s); 2.02 (3H, s).

APCI-MS m/z: 598 [MH⁺].

Example 76-Methyl-2-oxo-5-(1H-pyrrol-3-yl)-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

A mixture of5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(0.060 g, 0.10 mmol), 1-trimethylsilyl-1H-pyrrol-3-yl-boronic acid(0.033 g, 0.12 mmol), Pd(PPh₃)₄ (0.005 g, 4.34 nmol), DME (2 ml) andNa₂CO₃ (2 ml, 2M) was vigorously stirred under nitrogen in a sealed vialat 80° C. for 2 h. Another portion of1-trimethylsilyl-1H-pyrrol-3-yl-boronic acid (0.005 g) and Pd(PPh₃)₄(0.004 g) was added and the reaction was allowed to go for another hour.The mixture was allowed to cool and partitioned between EtOAc and water.The organic phase was collected and the aqueous phase was extracted withanother portion of EtOAc. The combined organic phases were washed withwater and brine, and were then dried over Na₂SO₄. Filtration andevaporation gave a crude oil which was purified on silica (heptane:EtOAc2:1 to 1:1 to 1:2), which after evaporation of pure fractions gave 0.08g (80%) of the intermediate as a white solid. A solution of this solidin THF (10 ml) containing tetrabutylammoniumfluoride trihydrate (0.025g, 0.08 mmol) was stirred at room temperature for 1 h. Evaporation andpurification on silica (heptane EtOAc 2:1 to 1:1 to 1:2) provided 0.02 g(47%) of the title compound as a white solid, which darkened onstanding.

¹H NMR (CDCl₃): δ10.12 (1H, t, J 5.5 Hz); 8.68 (1H, s); 8.53 (1H, bs);7.86 (2H, d, J 8.3 Hz); 7.79 (1H, d, J 7.8 Hz); 7.73 (1H, t, J 7.8 Hz);7.55 (1H, s); 7.52 (2H, d, J 8.3 Hz); 7.47 (1H, d, J 7.8 Hz); 6.87-6.82(2H, m); 6.28-6.24 (1H, m); 4.74-4.60 (2H, m); 3.00 (3H, s); 2.14 (3H,s).

APCI-MS m/z: 530.1 [MH⁺].

Using the general method of Example 2, the compounds of Example's 8 to12 were prepared:

Example 85-Furan-2-yl-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

¹H NMR (CDCl₃): δ 9.96 (1H, t, J 5.8 Hz); 8.85 (1H, s); 7.89 (2H, d, J8.7 Hz); 7.84 (1H, d, J 7.7 Hz); 7.77 (1H, t, J 7.7 Hz) 7.56 (1H, s);7.54 (2H, d, J 8.0 Hz); 7.48 (1H, d, J 7.7 Hz); 6.55-6.49 (2H, m);4.76-4.64 (2H, m); 3.03 (3H, s); 2.23 (3H, s).

APCI-MS m/z: 531.1 [MH⁺].

Example 96-Methyl-2-oxo-5-thiophen-3-yl-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

¹H NMR (CDCl₃): δ 10.02 (1H, t, J 5.9 Hz); 8.65 (1H, s); 7.88 (2H, d, J8.2 Hz); 7.82 (1H, d, J 7.8 Hz); 7.76 (1H, t, J 7.8 Hz); 7.57 (1H, s);7.53 (2H, d, J 8.2 Hz); 7.49 (1H, d, J 7.8 Hz); 7.46-7.42 (1H, m);7.27-7.25 (1H, m); 7.10 (1H, dd, J 5.0 Hz and 1.2 Hz); 4.75-4.62 (2H,m); 3.02 (3H, s); 2.07 (3H, s).

APCI-MS m/z: 547 [MH⁺].

Example 106-Methyl-2-oxo-5-thiophen-2-yl-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

¹H NMR (CDCl₃): δ 9.95 (1H, t, J 5.8 Hz); 8.68, (1H, s); 7.87 (2H, d, J8.5 Hz); 7.83 (1H, d, J 7.8 Hz); 7.75 (1H, t, J 7.8 Hz); 7.56 (1H, s);7.51 (2H, d, J 8.5 Hz); 7.48 (1H, d, J 8.5 Hz); 7.42-7.39 (1H, m);7.12-7.08 (1H, m); 7.04-7.01 (1H, m); 4.74-4.62 (2H, m); 3.01 (3H, s);2.11 (3H, s).

APCI-MS m/z: 547 [MH⁺].

Example 115-(3,5-Dimethyl-isoxazol-4-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

¹H NMR (CDCl₃): δ 9.93 (1H, t, J 5.8 Hz); 8.41 (1H, s); 7.86 (2H, d, J8.7 Hz); 7.82 (1H, d, J 7.7 Hz); 7.76 (1H, t, J 7.7 Hz); 7.54 (1H, bs);7.50 (2H, d, J 8.7 Hz); 7.49-7.44 (1H, m); 4.73-4.60 (2H, m); 3.01 (3H,s); 2.34-2.28 (3H, ds); 2.20-2.14 (3H, ds); 1.90 (3H, s).

APCI-MS m/z: 560.1 [MH⁺].

Example 125-(2,4-Dimethoxy-pyrimidin-5-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

¹H NMR (CDCl₃): δ 9.98 (1H, t, J 5.8 Hz); 8.49 (1H, s); 8.16 (1H, s);7.87 (2H, d, J 8.8 Hz); 7.83 (1H, d, J 7.8 Hz); 7.76 (1H, t, J 7.7 Hz);7.58 (1H, s); 7.52 (2H, d, J 8.2 Hz); 7.49 (1H, s); 4.76-4.60 (2H, m);4.07 (3H, s); 4.02 (3H, s); 3.02 (3H, s); 1.91 (3H, s).

APCI-MS m/z: 603.1 [MH⁺].

Example 135-(2,4-Dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-6-methyl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

A mixture of5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(0.075 g, 0.127 mmol), 2,4-di-tert-butyloxy-pyrimidine-5-boronic acid(0.044 g, 0.152 mmol), Pd(PPh₃)₄ (0.010 g, 8.69 nmol), DME (2 ml) andNa₂CO₃ (2 ml, 2M aqueous solution) was vigorously stirred under nitrogenin a sealed vial at 80° C. for 2 h. Then another portion of2,4-di-tert-butyloxy-pyrimidine-5-boronic acid (0.010 g) and Pd(PPh₃)₄(0.004 g) were added. After an additional hour the mixture was allowedto cool and was then partitioned between EtOAc and water. The organicphase was collected and the aqueous phase was extracted with anotherportion of EtOAc. The combined organic phases were washed with water andbrine, and dried over Na₂SO₄. Filtration and evaporation followed bypurification on silica (heptane:EtOAc 2:1 to 1:1 to 1:2) gave 0.060 g(69%) of the tert-butyl protected intermediate as a white solid. To asolution of the solid in THF (5 ml), TFA (5 ml) was added in one portionand the mixture was stirred for 30 minutes. The reaction mixture wasconcentrated and EtOAc was added to the residue. The obtained suspensionwas stirred for 10 minutes and the title compound was collected byfiltration. Yield 0.045 g (100%) as an off-white solid.

¹H NMR (DMSO-d₆): δ 11.31 (1H, s); 11.13 (1H, d, J 6.0); 9.91 (1H, t, J6.2 Hz); 8.24 (1H, s); 7.90 (1H, d, J 8.0 Hz); 7.86 (2H, d, J 8.4 Hz);7.81 (1H, d, J 7.8 Hz); 7.70 (1H, d, J 7.6 Hz); 7.65-7.59 (1H, m); 7.53(2H, d, J 8.4 Hz); 7.52 (1H, d, J 6.0 Hz); 4.58 (2H, d, J 6.2 Hz); 3.17(3H, s); 1.91 (3H, s).

APCI-MS m/z: 575.1 [MH⁺].

Example 146-Methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide a) Ethyl2-methyl-5-({[4-(methylsulfonyl)benzyl]amino}carbonyl)-6-oxo-1-[3-(trifluoromethyl)phenyl]-1,6-dihydropyridine-3-carboxylate

In a stainless-steel autoclave (100 ml) were placed5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(108.1 mg, 0.18 mmol), palladium(II)acetate (3.8 mg, 0.02 mmol),triphenylphosphine (10.3 mg, 0.04 mmol), triethylamine (2 ml, 14.4 mmol)and ethanol (6 ml). The reaction mixture was magnetically stirred at100° C. under a carbon monoxide pressure of 4 atmospheres overnight.After cooling, the solvent was evaporated off and the residue waspurified by preparative HPLC to give the title compound as a white solid(77.6 mg, 79%).

¹H NMR (CDCl₃): δ 9.73 (1H, t, J 5.9 Hz); 9.20 (1H, s); 7.90 (2H, d, J8.3 Hz); 7.85 (1H, d, J 7.9 Hz); 7.78 (1H, t, J 7.8 Hz); 7.53 (2H, d, J8.3 Hz); 7.50 (1H, s); 7.42 (1H, d, J 8.0 Hz); 4.69 (2H, t, J 5.9 Hz);4.38 (2H, q, J 7.2 Hz); 3.03 (3H, s); 2.50 (3H, s); 1.42 (3H, t, j 7.2Hz).

APCI-MS m/z: 537 [MH⁺].

b)5-(4-Methanesulfonyl-benzylcarbamoyl)-2-methyl-6-oxo-1-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridine-3-carboxylicacid

To a solution of ethyl2-methyl-5-({[4-(methylsulfonyl)benzyl]amino}carbonyl)-6-oxo-1-[3-(trifluoromethyl)phenyl]-1,6-dihydropyridine-3-carboxylate(0.70 g, 1.30 mmol) in THF (10 ml) and water (10 ml) was added NaOH (1M,2 ml, 2 mmol), and the mixture was stirred for 1 h at room temperature,monitoring the progress of the reaction by LC-MS. 20% conversion wasobserved and another portion of NaOH (1M, 1 ml, 1 mmol) was added, andthe reaction was allowed to run for another hour. This process wasrepeated until complete conversion of the ester was observed (normally3-4 hours). The outcome of the reaction is two compounds with the samemass, in a 95:5 proportion. The main product is the subtitle compound,and the other is a regioisomer. The reaction mixture was evaporated inorder to remove TIM, and the residual water solution was acidified andthen extracted into EtOAc. The organic phase was collected and driedover Na₂SO₄. Filtration and evaporation gave a crude product 0.60 g(90%) of a yellowish solid, which was used further without purification.A portion of the product was purified using preparative HPLC.

¹H NMR (CDCl₃): δ 9.90 (1H, t, J 6.2 Hz); 9.31 (1H, s); 7.89 (2H, d, J8.2 Hz); 7.84 (1H, d, J 8.0 Hz); 7.77 (1H, t, J 8.0 Hz); 7.51 (2H, J 8.5Hz); 4.49 (1H, s); 7.41 (1H, d, J 8.0 Hz); 4.92 (1H, bs); 4.78-4.63 (2H,m); 3.01 (3H, s); 2.53 (3H, s).

APCI-MS m/z: 509.2 [MH⁺].

c)5-(N¹-Acetyl-hydrazinocarbonyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

A solution of5-(4-methanesulfonyl-benzylcarbamoyl)-2-methyl-6-oxo-1-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridine-3-carboxylicacid (0.071 g, 0.14 mmol) in DCM (5 ml) containing SOCl₂ (5 ml) wasstirred in a sealed flask for 2 h and then concentrated. The obtainedsolid in 1,4-dioxane (5 ml, dried over molecular sieves) andacetylhydrazide (0.1 g, 1.35 mmol) were stirred for 10 minutes andconcentrated. The residue was purified by preparative HPLC giving 0.041g (52%) of the title compound as a white solid.

¹H NMR (DMSO-d₆): δ 10.26 (1H, s); 9.95 (1H, s); 9.79 (1H, t, J 6.0 Hz);8.50 (1H, s); 7.93 (1H, s); 7.93-7.90 (1H, m); 7.87 (2H, d, J 8.4 Hz);7.82 (1H, d, J 7.7 Hz); 7.74 (1H, d, J 8.0 Hz); 7.55 (2H, d, J 8.3 Hz);4.59 (2H, d, J 6.2 Hz); 3.17 (3H, s); 2.18 (3H, s); 1.91 (3H, s).

APCI-MS m/z: 565.2 [MH³⁰].

d)6-Methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

5-(N¹-Acetyl-hydrazinocarbonyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide (0.03 g, 0.053 mmol) andTMS-polyphosphate as a solution in DCM (prepared as described inSynthesis 1982, page 591-592) (3 ml) were stirred in a sealed vial at70° C. for 3 h. The cooled solution was diluted with DCM and washed withwater. The organic phase was collected and the aqueous phase wasextracted with another portion of DCM. The combined organic phase waswashed with brine, dried (Na₂SO₄), filtered, and concentrated. The solidmaterial was purified by preparative HPLC to give the title compound asa white solid (0.019 g, 66%).

¹H NMR (DMSO-d₆): δ 9.74 (1H, t, J 6.2 Hz); 8.78 (1H, s); 8.01 (1H, s);7.94 (1H, d, J 7.8 Hz); 7.87 (2H, d; J 8.1 Hz); 7.82 (1H, t, J 7.7 Hz);7.55 (2H, d, J 8.3 Hz); 4.61 (2H, d, J 6.1 Hz); 3.13 (3H, s); 2.59 (3H,s); 2.43 (3H, s).

APCI-MS m/z: 547.2 [MH⁺].

Using the general method of Example 14, the compounds of Examples 15 to19 were prepared:

Example 156-Methyl-2-oxo-5-(5-propyl-[1,3,4]oxadiazol-2-yl)-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

¹H NMR (DMSO-d₆): δ 9.75 (1H, t, J 6.33 Hz); 8.78 (1H, s); 8.00 (1H, s);7.94 (1H, d, J 8.1 Hz); 7.87 (2H, d, J 8.2 Hz); 7.86-7.83 (1H, m); 7.82(1H, t, J 8.4 Hz); 7.55 (2H, d, J 8.4); 4.60 (2H, d, J 6.1 Hz); 3.17(3H, s); 2.92 (2H, t, J 7.3 Hz); 2.42 (3H, s); 1.78 (2H, sext, J 7.3Hz); 0.99 (3H, t, J 7.3 Hz).

APCI-MS m/z: 575.2 [MH⁺].

Example 16{5-[5-(4-Methanesulfonyl-benzylcarbamoyl)-2-methyl-6-oxo-1-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridin-3-yl]-[1,3,4]oxadiazol-2-yl}-aceticacid ethyl ester

¹H NMR (DMSO-d₆): δ 9.73 (1H, t, J 6.0 Hz); 8.77 (1H, s); 8.01 (1H, s);7.94 (1H, d, J 7.8 Hz); 7.87 (2H, d, J 8.1 Hz); 7.86-7.80 (2H, m); 7.55(2H, d, J 8.1); 4.61 (2H, d, J 6.3 Hz); 4.30 (2H, s); 4.17 (2H, q, J 7.2Hz); 3.17 (3H, s); 2.44 (3H, s); 1.22 (3H, t, J 7.2 Hz).

APCI-MS m/z: 619.2 [MH⁺].

Example 175-(5-Cyanomethyl-[1,3,4]oxadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

¹H NMR (DMSO-d₆): δ 9.73 (1H, t, J 6.2 Hz); 8.76 (1H, s); 8.02 (1H, s);7.94 (1H, d, J 7.6 Hz); 7.87 (2H, d, J 8.1 Hz); 7.86-7.80 (2H, m); 7.55(2H, d, J 8.3 Hz); 4.70 (2H, s); 4.61 (2H, d, J 6.1 Hz); 3.17 (3H, s);2.42 (3H, s).

APCI-MS m/z: 572.2 [MH⁺].

Example 185-(5-Amino-[1,3,4]oxadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1)-1,2-dihydro-1-benzylamide

¹H NMR (DMSO-d₆): δ 9.81 (1H, t, J 6.1 Hz); 8.71 (1H, s); 8.00 (1H, s);7.94 (1H, d, J 8.0 Hz); 7.88 (2H, d, J 8.0 Hz) 7.86-7.82 (1H, m); 7.80(1H, d, J 8.3 Hz); 7.56 (2H, d, J 8.2 Hz); 7.29 (2H, s); 4.62 (2H, 6.09Hz); 3.18 (3H, s); 2.40 (3H, s).

APCI-MS m/z: 548.2 [MH⁺].

Example 195-(5-Amino-[1,3,4]thiadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

¹H NMR (DMSO-d₆): δ 9.83 (1H, t, J 6.2 Hz); 8.46 (1H, s); 7.99 (1H, s);7.92 (1H, d, J 7.4 Hz); 7.87 (2H, d, J 8.2); 7.83 (1H, d, J 7.6 Hz);7.79 (1H, d, J 8.0 Hz); 7.55 (2H, d, J 8.3 Hz); 7.42 (2H, s); 4.60 (2H,d, J 6.1 Hz); 3.17 (3H, s); 2.21 (3H, s).

APCI-MS m/z: 564.1 [MH⁺].

Example 205-(5-Ethylamino-[1,3,4]oxadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide a)5-Hydrazinocarbonyl-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-1-benzylamide

The title compound was prepared as described in Examples 14 (c) and 38(a).

APCI-MS m/z: 523.2 [MH⁺]. Retention time 1.72 minutes.

b)5-({2-[(Ethylamino)carbonyl]hydrazino}carbonyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

To5-hydrazinocarbonyl-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide (0.030 g, 0.057 mmol) in 1,4-dioxane(10 ml) was added ethyl isocyanate (0.016 g, 0.23 mmol) and the mixturewas stirred at room temperature for 1 h. The mixture was evaporated andthe residue was purified by preparative HPLC giving 0.015 g (44%) of thetitle compound.

¹H NMR (CDCl₃): δ 9.96-9.87 (1H, m); 8.82 (1H, s); 7.88 (1H, d, J 8.2Hz); 7.84 (2H, d, J 7.9 Hz); 7.83-7.80 (1H, m); 7.77 (1H, t, J 7.9 Hz);7.52 (1H, s); 7.47 (2H, d, J 8.2 Hz); 7.47-7.41 (1H, m); 4.70-4.55 (2H,m); 3.23 (2H, q, J 6.8 Hz); 3.01 (3H, s); 2.31 (3H, s); 1.11 (3H, t, J7.1 Hz).

APCI-MS m/z: 594.2 [MH⁺].

c)5-(5-Ethylamino-[1,3,4]oxadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

The title compound was prepared from5-({2-[(ethylamino)carbonyl]hydrazino}carbonyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamideusing an analogous method to that described in Example 14 (d).

¹H NMR (DMSO-d₆): δ 9:78 (1H, t, J 6.0 Hz); 8.69 (1H, s); 7.99 (1H, s);7.93 (1H, d, J 7.5 Hz); 7.87 (2H, d, J 8.5 Hz); 7.84 (1H, d, J 8.0 Hz);7.81-7.75 (2H, m); 7.55 (2H, d, J 8.1 Hz); 4.60 (2H, d, J 6.1 Hz); 3.26(2H, p, J 6.6 Hz); 3.17 (3H, s); 2.38 (3H, s); 1.18 (3H, t, J 7.1 Hz).

APCI-MS m/z: 576.3 [MH⁺].

Example 215-(5-N,N-Dimethylamino-[1,3,4]oxadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide a)5-({2-[(N,N-Dimethylamino)carbonyl]hydrazino}-carbonyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

To5-hydrazinocarbonyl-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide (0.030 g, 0.057 mmol) in THF (10 ml)was added N,N-dimethylcarbamoyl chloride (0.0247 g, 0.23 mmol) and themixture was stirred at 50° C. for 3 h. The mixture was evaporated andthe residue was purified by preparative HPLC giving 0.020 g (60%) of thetitle compound.

¹H NMR (DMSO-d₆): δ 9.92 (1H, bs); 9.80 (1H, t, 6.2 Hz); 8.50 (1H, s);8.48 (1H, s); 7.94-7.89 (2H, m); 7.87 (2H, d, J 8.5 Hz); 7.82 (1H, d, J8.2 Hz); 7.73 (1H, d, J 7.8 Hz); 7.55 (2H, d, J 8.5 Hz); 4.59 (2H, d, J6.0 Hz); 3.17 (3H, s); 2.8 (6H, s); 2.19 (3H, s).

APCI-MS m/z: 594.1 [MH⁺].

b)5-(5-N,N-Dimethylamino-[1,3,4]oxadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

The title compound was prepared from5-({2-[(N,N-dimethylamino)carbonyl]hydrazino}carbonyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamideusing the general method described in Example 14 (d).

¹H NMR (DMSO-d₆): δ 9.79 (1H, t, J 6.2 Hz); 8.69 (1H, s); 8.00 (1H, s);7.93 (1H, d, J 7.9 Hz); 7.87 (2H, d, J 8.4 Hz); 7.85 (1H, t, J 7.7 Hz);7.80 (1H, d, J 7.7 Hz); 7.55 (2H, d, J 8.4 Hz); 4.59 (2H, d, J 6.2 Hz);3.17 (3H, s); 3.06 (6H, s); 2.36 (3H, s).

APCI-MS m/z: 576.3 [MH⁺].

Example 226-Methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-(pyrazin-2-yl)-1-[3-trifluoro-methyl)phenyl]-1,2-dihydropyridine-3-carboxamide

Tris(dibenzylidene-acetone)dipalladium(0) (1 mg) was added to5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoro-methyl)phenyl]-1,2-dihydropyridine-3-carboxamide(Example 1 (d), 20 mg, 0.034 mmol), 2-(tributylstannyl)pyrazine (25 mg,0.068 mmol) and triphenylphosphine (1.6 mg, 0.006 mmol) in toluene (1.5ml) under argon and the mixture was stirred in a sealed vial at 100° C.overnight. After cooling, the mixture was filtered through celite andevaporated. The residue was dissolved in toluene and ether was added.The precipitate was filtered off and dried in vacuo (5 mg, 27%).

¹H NMR (CDCl₃): δ 9.93-9.85 (1H, m); 8.82-8.77 (2H, m); 8.68-8.64 (1H,m); 8.60 (1H, d, J 14.0 Hz); 7.91-7.73 (4H, m); 7.59-7.46 (4H, m);4.76-4.62 (2H, m); 3.01 (3H, s); 2.18 (3H, s).

APCI-MS m/z 543.3 [MH⁺].

Example 236-Methyl-5-(oxazol-2-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoro-methyl)phenyl]-1,2-dihydropyridine-3-carboxamide(0.10 g, 0.169 mmol), 2-tributylstannyl-oxazole (0.12 g, 0.33 mmol,prepared according to literature procedures), Pd(PPh₃)₄ (0.015 g, 0.012mmol) and dimethoxyethane (DME, 2.5 ml) and a magnetic stirrer bar wereplaced in a vial. The suspension was degassed and the vial sealed, andsubsequently heated (100° C.) with stirring for 4 h. LC-MS confirmed theconversion of the iodide to the desired product, and the solvents wereremoved in vacuo. Purification on preparative HPLC afforded the titlecompound (0.06 g, 67%) as a white solid after freeze-drying the purefractions.

¹H NMR (DMSO-d₆): δ 9.79 (1H, t, J 6.2 Hz); 8.91 (1H, s); 8.28 (1H, s);7.99 (1H, s); 7.93 (1H, d, J 7.9 Hz); 7.87 (2H, d, J 8.2 Hz); 7.85 (1H,t, J 7.9 Hz); 7.80 (1H, d, J 7.8 Hz); 7.55 (2H, d, J 8.2 Hz); 7.42 (1H,s); 4.67-4.55 (2H, m); 3.17 (3H, s); 2.46 (3H, s).

APCI-MS m/z: 532.2 [MH⁺].

Example 256-Methyl-5-(1-methyl-1H-imidazol-2-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoro-methyl)phenyl]-1,2-dihydropyridine-3-carboxamide(0.06 g, 0.1 mmol), 1-methyl-2-tributylstannyl-1H-imidazole (0.11 g, 0.5mmol, prepared according to literature procedures), Pd(PPh₃)₄ (0.015 g,0.012 mmol), DME (2 ml) and a magnetic stirrer bar were placed in avial. The suspension was degassed and the vial was sealed, andsubsequently heated (100° C.) with stirring overnight. LC-MS confirmedthe conversion of the iodide to the desired product, and the solventswere removed in vacuo. Purification on preparative HPLC afforded thetitle compound (0.005 g, 10%) as a white solid after freeze-drying thepure fractions.

¹H NMR (DMSO-d₆): δ 9.88 (1H, t, J 6.2 Hz); 8.30 (1H, s); 8.03 (1H, s);7.94-7.89 (1H, m); 7.87 (2H, d, J 8.5 Hz); 7.85-7.81 (2H, m); 7.55 (2H,d, J 8.5 Hz); 7.31 (1H, s); 7.06 (1H, s); 4.66-4.55 (2H, m); 3.58 (3H,s); 3.17 (3H, s); 1.85 (3H, s).

APCI-MS m/z: 545.2 [MH⁺].

Example 266-Methyl-2-oxo-5-(1H-pyrazol-4-yl)-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide(0.080 g, 0.135 mmol), 4-tributylstannyl-1-trityl-1H-pyrazole (0.08 g,0.13 mmol, prepared according to literature procedures), Pd(PPh₃)₄(0.020 g, 0.017 mmol), DME (3 ml) and a magnetic stirrer bar were placedin a vial. The reactor was degassed, the vial sealed and the reactionwas heated (95° C.) with stirring overnight. LC-MS showed that almostall starting iodide had been consumed to give a main product. The crudemixture was evaporated and the residual oil was purified on silica(heptane:EtOAc 1:2), giving 0.060 g of the intermediate trityl protectedproduct. The intermediate was dissolved in DCM (3 ml) and TFA (3 ml) wasadded. The mixture was heated (50° C.) with stirring for 30 minutes. Thereaction was quenched by the addition of methanol (5 ml). Purificationon preparative HPLC gave the title compound (0.016 g, 22%) as a whitesolid after freeze-drying the pure fractions.

¹H NMR (DMSO-d₆): δ 9.98 (1H, t, J 6.2 Hz); 8.38 (1H, s); 7.94 (1H, s);7.91 (1H, d, J 8.1 Hz); 7.87 (2H, d, J 8.3 Hz); 7.84-7.80 (2H, m); 7.75(1H, d, J 7.9 Hz); 7.55 (2H, d, J 8.4 Hz); 5.76 (1H, s); 4.64-4.55 (2H,m); 3.17 (3H, s); 2.06 (3H, s).

APCI-MS m/z: 531.1 [MH⁺].

Example 276-Methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-pyrimidin-2-yl-1-[3-(trifluoro-methyl)phenyl]-1,2-dihydropyridine-3-carboxamide

Tris(dibenzylideneacetone)-dipalladium(0) (1 mg) was added to5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide(20 mg, 0.034 mmol), 2-(tributyl-stannyl)pyrimidine (25 mg, 0.068 mmol)and triphenylphosphine (1.9 mg, 0.007 mmol) in toluene (1.6 ml) underargon and the mixture was stirred at 100° C. overnight. After cooling,the mixture was filtered through celite and evaporated. The residue waspurified by preparative HPLC. Pure fractions were freeze-dried to givethe title compound (5 mg, 27%).

¹H NMR (CDCl₃): δ 9.91-9.85 (1H, m); 9.28 (1H, s); 8.84 (2H, d, 15.2Hz); 7.90-7.73 (4H, m); 7.57-7.45 (4H, m); 7.29-7.25 (1H, m); 4.76-4.62(2H, m); 3.01 (3H, s); 2.40 (3H, s).

APCI-MS m/z: 543.1 [MH⁺].

Example 286-Methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-1-(trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide(0.06 g, 0.1 mmol), 1-methyl-5-trimethylstannyl-1H-pyrazole (0.07 g, 0.3mmol, prepared according to literature procedures), Pd(PPh₃)₄ (0.015 g,0.012 mmol), DME (2 ml) and a magnetic stirrer bar were placed in avial. The suspension was degassed and the vial was sealed, andsubsequently heated (100° C.) with stirring overnight. LC-MS confirmedthe conversion of the iodide to the desired product, and the solventswere removed in vacuo. Purification on silica (heptane:EtOAc 1:2 to 1:3)afforded the title compound (0.040 g, 75%) as a white solid, which wassubsequently freeze-dried.

¹H NMR (DMSO-d₆): δ 9.89 (1H, t, J 6.2 Hz); 8.21 (1H, s); 8.02 (1H, s);7.92 (1H, d, J 7.31 Hz); 7.87 (2H, d, 18.3 Hz); 7.85-7.80 (2H, m); 7.54(2H, d, J 8.3 Hz); 7.53 (1H, d, J 1.8 Hz); 6.33 (1H, d, J 1.8 Hz);4.66-4.55 (2H, m); 3.72 (3H, s); 3.17 (3H, s); 1.82 (3H, s).

APCI-MS m/z: 545.2 [MH⁺].

Example 296-Methyl-5-(3-methylisoxazol-4-yl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(25 mg, 0.042 mmol), tetrakis(triphenylphosphine) palladium (2.5 mg,0.0022 mmol) and 3-methyl-4-(tributylstannyl)isoxazole [synthesized asdescribed by D. Uchiyama in Heterocycles, 43, 6, 1301, 1996] (32 mg,0.086 mmol) were mixed in DME (0.45 ml) in an argon filled vial. Thevial was closed and heated with stirring at 100° C. for 24 h. Thereaction mixture was poured into a mixture of ethyl acetate and water.The mixture was shaken, the water phase was removed and the organicphase was dried over sodium sulphate. The product was purified bypreparative HPLC. Yield: 12 mg, 0.022 mmol (52%).

¹H NMR (DMSO-d₆): δ 9.91 (1H, t, J 6.0 Hz); 8.24 (1H, s); 8.96 (1H, s);7.98-7.77 (6H, m); 7.54 (2H, d, J 8.4 Hz); 4.59 (2H, d, J 6.2 Hz); 3.17(3H, s); 2.21 (3H, s); 1.88 (3H, s).

APCI-MS m/z: 546.5 [MH⁺].

Example 306-Methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(0.236 g, 0.4 mmol), acetamide oxime (0.088 g, 1.2 mmol), Pd(PPh₃)₂Cl₂(0.014 g, 0.020 mmol), triethylamine (0.081 g, 0.8 mmol), toluene (15ml) and a magnetic stirrer bar were loaded into a pressure safe steelreactor. The reactor was degassed with CO, and when all air had beenremoved, a 4 atmospheres pressure of CO was applied, and the reactor washeated to 95° C. The reaction was allowed to proceed overnight. LC-MSshowed that almost all starting iodide had been consumed to give a mainproduct. The crude mixture was evaporated and the residual oil waspartitioned between EtOAc and water. The organic phase was collected,and was dried and evaporated. Purification on silica (heptane:EtOAc 1:2)gave pure material (0.083 g, 38%) as a white solid.

¹H NMR (DMSO-d₆): δ 9.68 (1H, t, J 6.2 Hz); 8.91 (1H, s); 8.01 (1H, s);7.95 (1H, d, J 8.1 Hz); 7.87 (2H, d, J 8.02 Hz); 7.86 (1H, t, J 7.16Hz); 7.81 (1H, d, J 7.86 Hz); 7.55 (2H, d, J 8.3 Hz); 4.67-4.55 (2H, m);3.17 (3H, s); 2.47 (3H, s); 2.41 (3H, s).

APCI-MS m/z: 547.0 [MH⁺].

Example 316-Methyl-5-(3-methylisoxazol-5-yl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was synthesized in the same way as Example 29 butstarting from5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(50 mg, 0.085 mmol), tetrakis(triphenylphosphine)palladium (5 mg, 0.0043mmol) and 3-methyl-5-(tributylstannyl)isoxazole [synthesized asdescribed in Tetrahedron, 47, 28, 5111, 1991] (63 mg, 0.169 mmol) in DME(0.85 ml). Yield: 15 mg, 0.033 mmol (39%).

¹H NMR (DMSO-d₆): δ 9.79 (1H, t, J=6.0 Hz); 8.57 (1H, s); 7.99 (1H, s);7.94-7.79 (5H, m); 7.55 (2H, d, J=8.4 Hz); 6.67 (1H, s); 4.60 (2H, d,J=6.2 Hz); 3.17 (3H, s); 2.30 (3H, s); 2.17 (3H, s).

APCI-MS m/z: 546.4 [MH⁺].

The compounds of Examples 32 to 37 were prepared using analogous methodsto those described in Examples 1 (a) to 1 (d) and 2.

Example 325-(3,5-Dimethylisoxazol-4-yl)-N-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 10.12 (1H, bt); 8.44 (1H, s); 7.86-7.67 (4H, m); 7.56(1H, bs); 7.51-7.47 (3H, m); 4.76-4.66 (2H, m); 3.21-3.11 (1H, m); 2.34(3H, d, J 6.8 Hz); 2.20 (3H, d, J 6.8 Hz); 1.93 (3H, s): 1.27 (6H; d, J7.0 Hz).

APCI-MS m/z: 588 [MH⁺].

Example 335-(3,5-Dimethylisoxazol-4-yl)-N-[4-(ethylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 10.15 (1H, bt); 8.43 (1H, s); 7.86-7.83 (3H, m); 7.78(1H, bt); 7.57 (1H, bs) 7.53-7.47 (3H, m); 4.73-4.69 (2H, m); 3.09 (2H,q, J 7.4 Hz); 2.34 (3H, d, J 6.9 Hz); 2.20 (3H, d, J 6.9 Hz); 1.94 (3H,s): 1.26 (3H, t, J 7.4 Hz).

APCI-MS m/z: 574 [MH⁺].

Example 34N-[4-(Cyclopropylsulfonyl)benzyl]-5-(3,5-dimethylisoxazol-4-yl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 10.06 (1H, bt); 8.43 (1H, s); 7.88-7.76 (4H, m); 7.56(1H, bs) 7.51-7.47 (3H, m); 4.74-4.63 (2H, m);); 2.45-2.38 (1H, m); 2.33(3H, d, J 6.7 Hz); 2.19 (3H, d, J 6.7 Hz); 1.92 (3H, s): 1.35-1.30 (2H,m); 1.07-0.99 (2H, m).

APCI-MS m/z: 586 [MH⁺].

Example 351-(3-Cyanophenyl)-5-(3,5-dimethylisoxazol-4-yl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

¹H NMR (CDCl₃): δ 9.88 (1H, bt); 8.44 (1H, s); 7.90-7.86 (3H, m); 7.77(1H, bt); 7.62-7.51 (4H, m); 4.74-4.63 (2H, m); 3.02 (3H, s); 2.33 (3H,d, J 5.7 Hz); 2.19 (3H, d, J 5.6 Hz); 1.93 (3H, s).

APCI-MS m/z: 517 [MH⁺].

Example 361-(3-Chlorophenyl)-5-(3,5-dimethyl-isoxazol-4-yl)-6-methyl-2-oxo-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

¹H NMR (CDCl₃): δ 9.98 (1H, bt); 8.42 (1H, s); 7.88 (2H, d, J 8.4 Hz);7.57-7.52 (4H, m); 7.30-7.29 (1H, m); 7.19-7.17 (1H, m); 4.68 (2H, d, J5.6 Hz); 3.02 (3H, s); 2.32 (3H, d, J 4.0 Hz); 2.18 (3H, d, J 4.2 Hz);1.95 (3H, s).

APCI-MS m/z: 526 [MH⁺].

Example 375-(3,5-Dimethyl-isoxazol-4-yl)-6-methyl-2-oxo-1-m-tolyl-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

¹H NMR (CDCl₃): δ 10.11 (1H, bt); 8.40 (1H, s); 7.87 (2H, d, J 8.4 Hz);7.54-7.47 (3H, m); 7.35 (1H, d, J 7.7 Hz); 7.06-7.03 (2H, m); 4.67 (2H,d, J 5.9 Hz); 3.02 (3H, s); 2.46 (3H, s); 2.32 (3H, d, J 2.5 Hz); 2.18(3H, d, J 3.0 Hz); 1.93 (3H, s).

APCI-MS m/z: 506 [MH⁺].

Example 385-(5-Isopropyl-[1,3,4]oxadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide a)5-Hydrazinocarbonyl-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

The compound obtained in Example 14 (b) (0.051 g, 0.14 mmol) in DCM (5ml) was treated with SOCl₂ (5 ml), and the flask was sealed and stirredmagnetically for 2 h, when LC-MS showed that the reaction was complete.The crude mixture was evaporated in vacuo, giving the intermediate acidchloride as a yellow solid. The solid was dissolved in 1,4-dioxane (5ml, dried over molecular sieves) and hydrazine hydrate (0.05 g, 1.0mmol) was added. The mixture was stirred for 10 minutes, and LC-MSshowed complete formation of the title compound. The mixture wasconcentrated in vacuo and the residue was purified by preparative HPLCgiving the title compound (0.036 g, 70%) as a white solid afterfreeze-drying the pure fractions.

APCI-MS m/z: 523.2 [MH⁺].

b)5-(N¹-Isobutyryl-hydrazinocarbonyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

The compound obtained in step (a) (0.025 g, 0.047 mmol) in dry THF (10ml) was stirred and isobutyric anhydride (0.040 g, 0.25 mmol) was added.The obtained mixture was stirred for 15 minutes, and LC-MS showedcomplete conversion of the starting material to the desired amide. Thesolvent was evaporated and the residue was purified by preparative HPLCgiving the subtitle compound (0.024 g, 85%) as a white powder afterfreeze-drying the pure fractions.

¹H NMR (DMSO-d₆): δ 10.25 (1H, bs); 9.89 (1H, bs); 9.79 (1H, t, J 6.2Hz); 8.50 (1H, s); 7.53 (1H, s); 7.94-7.90 (1H, m); 7.87 (2H, d, J 8.5Hz); 7.84 (1H, t, J 7.7 Hz); 7.74 (1H, d, J 7.7 Hz); 7.55 (2H, d, J 8.3Hz); 4.63-4.56 (2H, m); 3.18 (3H, s); 2.55-2.49 (1H, p, J 6.8 Hz); 2.18(3H, s); 1.08 (6H, d, J 6.8 Hz).

APCI-MS m/z: 593.2 [MH⁺].

c)5-(5-Isopropyl-[1,3,4]oxadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

The compound obtained in step (b) (0.02 g, 0.034 mmol) inTMS-polyphosphate (3 ml, PPSE in DCM, Synthesis 1982, page 591-592) wasstirred in a sealed vial and heated at 70° C. for 3 h. LC-MS showedcomplete conversion of the linear starting material to a compound withthe expected MW. The cooled solution was diluted with DCM (10 ml) andwas washed with water (10 ml). The organic phase was collected and theaqueous phase was extracted with another portion of DCM (10 ml). Thecombined organic phase was washed with brine and was then dried withNa₂SO₄. Filtration and evaporation of the solution gave a white solid.Purification of this material by preparative HPLC provided purefractions which were freeze-dried. The title compound was obtained as awhite solid (0.015 g, 77%).

¹H NMR (DMSO-d₆): δ 9.76 (1H, t, J 6.29 Hz); 8.77 (1H, s); 8.01 (1H, s);7.94 (1H, d, J 7.6 Hz); 7.87 (2H, d, J 8.6 Hz); 7.84-7.78 (2H, m); 7.55(2H, d, J 8.4 Hz); 4.65-4.56 (2H, m); 3.30 (1H, p, J 6.9 Hz); 3.18 (3H,s); 2.41 (3H, s); 1.36 (6H, d, J 7.0 Hz).

APCI-MS Mk: 575.2 [MH⁺].

Example 396-Methyl-5-[1,3,4]oxadiazol-2-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide a)5-[N¹-(Formyl-hydrazinocarbonyl]-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

The compound obtained in Example 38 (a) (0.025 g, 0.048 mmol) in dry THF(10 ml) was stirred and mixed formylacetyl anhydride (0.06 g, 0.68 mmol;prepared according to literature procedures) was added. The mixture wasstirred for 20 minutes and LC-MS showed full conversion of the startingmaterial. Evaporation and purification on preparative HPLC, andsubsequent freeze-drying, afforded the sub-title compound (0.022 g, 83%)as a white powder.

¹H NMR (DMSO-d₆): δ 10.43 (1H, s); 10.13 (1H, s); 9.79 (1H, t, J 6.2Hz); 8.52 (1H, s); 8.11 (1H, s); 7.93 (1H, s); 7.94-7.89 (1H, s); 7.87(2H, d, J 8.65 Hz); 7.87 (1H, d, J 8.21); 7.74 (1H, d, J 8.21 Hz); 7.55(2H, d, J 8.21 Hz); 4.63-4.54 (2H, m); 3.17 (3H, s); 2.18 (3H, s).

APCI-MS m/z: 551.2 [MH⁺].

b)6-Methyl-5-[1,3,4]oxadiazol-2-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

The title compound was prepared according to the procedure described inExample 38 (c) starting from 0.020 g (0.036 mmol) of the compoundobtained in step (a). The title compound was obtained as a white solid(0.010 g, 52%) after purification on preparative HPLC and freeze-dryingof the pure fractions.

¹H NMR (DMSO-d₆): δ 9.74 (1H, t, J 6.3 Hz); 9.38 (1H, s); 8.82 (1H, s);8.01 (1H, s); 7.94 (1H, d, J 7.7 Hz); 7.87 (2H, d, J 8.0 Hz); 7.87-7.84(1H, m); 7.81 (1H, d, J 7.9 Hz); 7.55 (2H, d, J 8.0 Hz); 4.65-4.55 (2H,m); 3.17 (3H, s); 2.45 (3H, s).

APCI-MS m/z: 533.2 [MH⁺].

Example 405-(5-Hydroxy-[1,3,4]oxadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide a)N¹-[5-(4-Methanesulfonyl-benzylcarbamoyl)-2-methyl-6-oxo-1-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridine-3-carbonyl]-hydrazinecarboxylicacid ethyl ester

The compound obtained in Example 38 (a) (0.025 g, 0.048 mmol) in dry THF(2 ml) was stirred and diethyl pyrocarbonate (0.023 g, 0.14 mmol) wasadded. The vial was sealed and was stirred at 40° C. for 3 h, monitoringthe reaction by LC-MS. The mixture was evaporated and was then purifiedby preparative HPLC, giving the sub-title compound (0.023 g, 80%) as awhite solid after freeze-drying the pure fractions.

¹H NMR (DMSO-d₆): δ 10.23 (1H, s); 9.79 (1H, t, J 6.1 Hz); 9.23 (1H, s);8.47 (1H, s); 7.94 (1H, s); 7.94-7.89 (1H, d, J 8.2 Hz); 7.87 (2H, d, J8.4 Hz); 7.82 (1H, d, J 7.7 Hz); 7.74 (1H, d, J 7.8 Hz); 7.54 (2H, d, J8.4 Hz); 4.65-4.55 (2H, m); 4.14-4.01 (2H, m); 3.17 (3H, s); 2.16 (3H,s); 1.25-1.15 (3H, m).

APCI-MS m/z: 595.2 [MH⁺].

b)5-(5-Hydroxy-[1,3,4]oxadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

The title compound was prepared according to the procedure described inExample 38 (c) starting from 0.015 g (0.025 mmol) of the compoundobtained in step (a). The reaction time was 4 days. The product wasobtained as a white solid (0.008 g, 58%) after purification onpreparative HPLC and freeze-drying of the pure fractions.

¹H NMR (DMSO-d₆): δ 12.61 (1H, bs); 9.73 (1H, t, J 6.2 Hz); 8.63 (1H,s); 7.99 (1H, s); 7.93 (1H, d, J 8.0 Hz); 7.87 (2H, d, J 8.2 Hz); 7.85(1H, t, J 7.8 Hz); 7.78 (1H, d, J 7.8 Hz); 7.55 (2H, d, J 8.2 Hz);4.64-4.55 (2H, m); 3.17 (3H, s); 2.30 (3H, s).

APCI-MS m/z: 549.1 [MH⁺].

Example 416-Methyl-5-(5-methyl-4H-[1,2,4]triazol-3-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methylsulfonyl-benzylamide

The compound of Example 38 (a) (0.017 g, 0.0325 mmol), toluene (1 ml),NMP (0.5 ml), triethylamine (0.5 ml), ethyl acetamidate hydrochloride(0.030 g, 0.24 mmol) and a magnetic stirrer bar were placed in a glassvial. The vial was sealed and the mixture was heated with stirring at100° C. overnight. The mixture was allowed to cool and was thenconcentrated in vacuo. Purification by preparative HPLC and subsequentfreeze-drying of the pure fractions afforded the title compound (0.005g, 28%) as a white solid.

¹H NMR (DMSO-d₆): δ 13.79 (1H, bs); 9.89 (1H, t, J 6.0 Hz); 8.99 (1H,s); 7.97 (1H, s); 7.90 (1H, d, J 8.0 Hz); 7.87 (2H, d, J 8.2 Hz); 7.83(1H, t, J 7.9 Hz); 7.78 (1H, d, J 7.9 Hz); 7.55 (2H, d, J 8.3 Hz);4.67-4.55 (2H, m); 3.17 (3H, s); 2.41 (3H, s); 2.41 (3H, s).

APCI-MS m/z: 546.2 [MH⁺].

Example 425-(4,5-Dimethyl-4H-[1,2,4]triazol-3-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

A solution of POCl₃ (0.030 g, 0.2 mmol) in CHCl₃ (1 ml) and pyridine (1ml) was added to N-methylacetamide (0.015 g, 0.2 mmol) and the mixturewas cooled in an ice-water bath and stirred for 90 minutes. To thissolution was added a solution of5-hydrazinocarbonyl-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide (Example 38 (a), 0.040 g, 0.076 mmol)in CHCl₃ (2 ml) and the mixture was stirred overnight at roomtemperature. Purification by preparative HPLC gave the linearintermediate (0.020 g). This material was suspended in EtOAc (2 ml) andwas heated (90° C.) with stirring for 4 h, giving rise to a mixture ofthree components. This mixture was purified on preparative HPLC givingthe title compound (0.003 g, 7%) after freeze-drying the pure fractions.

¹H NMR (DMSO-d₆): δ 9.89 (1H, t, J 6.1 Hz); 8.29 (1H, s); 8.04 (1H, s);7.94-7.89 (1H, m); 7.87 (2H, d, J 8.6 Hz); 7.87-7.83 (2H, m); 7.55 (2H,d, J 8.3 Hz); 4.66-4.55 (2H, m); 3.45 (3H, s); 3.17 (3H, s); 2.39 (3H,s); 1.87 (3H, s).

APCI-MS m/z: 560.2 [MH⁺].

Example 435-(5-Methoxymethyl-[1,3,4]oxadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide a)5-[N¹-(2-Methoxy-acetyl)-hydrazinocarbonyl]-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

The compound obtained in Example 38 (a) (0.028 g, 0.053 mmol) in dry THF(2 ml) was treated with triethylamine (0.020 g, 0.20 mmol) and2-methoxyacetyl chloride (0.02 g, 0.18 mmol). The mixture was stirredfor 5 minutes and LC-MS showed complete conversion of the startingmaterial to a mixture of three compounds. The reaction was quenched bythe addition of MeOH, and subsequent evaporation and purification onpreparative HPLC afforded the subtitle compound (0.015 g, 47%) as awhite solid after freeze-drying the pure fractions.

¹H NMR (DMSO-d₆): δ10.29 (1H, s); 9.95 (1H, s); 9.79 (1H, t, J 6.3 Hz);8.51 (1H, s); 7.93 (1H, s); 7.94-7.89 (1H, m); 7.87 (2H, d, J 8.3 Hz);7.82 (1H, d, J 7.8 Hz); 7.74 (1H, d, J 7.7 Hz); 7.55 (2H, d, J 8.1 Hz);4.65-4.55 (2H, m); 3.97 (2H, s); 3.36 (3H, s); 3.17 (3H, s); 2.18 (3H,s).

APCI-MS m/z: 595.2 [MH⁺].

b)5-(5-Methoxymethyl-[1,3,4]oxadiazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

Prepared according to the procedure described in Example 38 (c) startingfrom 0.015 g (0.025 mmol) of the compound obtained in step (a). Thetitle compound (0.011 g, 80%) was obtained as a white solid afterpurification on preparative HPLC and freeze-drying of the purefractions.

¹H NMR (DMSO-d₆): δ 9.73 (1H, t, J 6.1 Hz); 8.79 (1H, s); 8.01 (1H, s);7.94 (1H, d, J 7.9 Hz); 7.87 (2H, d, J 8.14 Hz); 7.86-7.84 (1H, m); 7.71(1H, d, J 7.9 Hz); 7.56 (2H, d, J 8.1 Hz); 4.75 (2H, s); 4.65-4.55 (2H,m); 3.39 (3H, s); 3.17 (3H, s); 2.45 (3H, s).

APCI-MS m/z: 577.2 [MH⁺].

Example 44N-[4-(Isopropylsulfonyl)benzyl]-6-methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was prepared by an analogous method to that describedin Example 14.

¹H NMR (CDCl₃): δ 9.96 (1H, bt); 9.08 (1H, s); 7.89-7.78 (4H, m);7.55-7.45 (4H, m); 4.78-4.65 (2H, m); 3.20-3.13 (1H, m); 2.68 (3H, s);2.62 (3H, s); 1.28 (6H, d, J 6.9 Hz).

APCI-MS m/z: 575 [MH⁺].

Example 45N-[4-(Ethylsulfonyl)benzyl]-6-methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was prepared by an analogous method to that describedin Example 14.

¹H NMR (CDCl₃): δ 9.80-9.71 (1H, m); 9.09 (1H, s); 7.90-7.74 (4H, m);7.56-7.42 (4H, m); 4.79-4.63 (2H, m); 3.08 (2H, q, J 7.5 Hz); 2.64 (3H,s); 2.62 (3H, s); 1.27 (3H, t, J 7.4 Hz).

APCI-MS m/z: 561.1 [MH⁺].

Example 46N-[4-(Cyclopropylsulfonyl)benzyl]-6-methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was prepared by an analogous method to that describedin Example 14.

¹H NMR (CDCl₃): δ 9.74 (1H, bt); 9.09 (1H, s); 7.87-7.77 (4H, m);7.54-7.45 (4H, m); 4.75-4.64 (2H, m); 2.64 (3H, s); 2.62 (3H, s);2.46-2.39 (1H, m); 1.35-1.31 (2H, m); 1.04-0.99 (2H, m).

APCI-MS m/z: 573 [MH⁺].

Example 476-Methyl-5-[1,3,4]oxadiazol-2-yl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-(propane-2-sulfonyl)-benzylamide

The title compound (0.025 g, 64%) was prepared by an analogous method tothat described in Example 39.

¹H NMR (DMSO-d₆): δ 9.75 (1H, t, J 6.2 Hz); 9.38 (1H, s); 8.82 (1H, s);8.02 (1H, s); 7.94 (1H, d, J 7.5 Hz); 7.89-7.82 (2H, m); 7.80 (2H, d, J8.2 Hz); 7.56 (2H, d, J 8.2 Hz); 4.68-4.56 (2H, m); 3.37 (1H, p, J 6.8Hz); 2.45 (3H, s); 1.13 (6H, d, J 6.2 Hz).

APCI-MS m/z: 561.2 [MH⁺].

Example 486-Methyl-5-[1,3,4]oxadiazol-2-yl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-cyclopropanesulfonyl-benzylamide

The title compound (0.023 g, 80%) was prepared by an analogous method tothat described in Example 39.

¹H NMR (DMSO-d₆): δ 9.74 (1H, t, J 6.2 Hz); 9.38 (1H, s); 8.82 (1H, s);8.01 (1H, s); 7.94 (1H, d, J 7.7 Hz); 7.89-7.80 (2H, m); 7.84 (2H, d, J8.2 Hz); 7.55 (2H, d, J 8.2 Hz); 4.66-4.56 (2H, m); 2.84-2.77 (1H, m);2.44 (3H, s); 1.12-1.05 (2H, m); 1.05-0.97 (2H, m).

APCI-MS m/z: 559.2 [MH⁺].

Example 506-Methyl-5-(2-methyl-1,3-oxazol-4-yl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidea)5-(1-Butoxyvinyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(Example 1 (d), 101.5 mg, 0.17 mmol),bis[1,2-bis(diphenylphosphino)ethane]-palladium (0) (16.5 mg, 18.3μmmol), n-butyl vinyl ether (60 μl, 0.46 mmol), triethylamine (0.5 ml,3.6 mmol) and DMF (6 ml) were placed in a Schlenk vessel equipped with amagnetic stirring bar. The vessel was purged with argon, sealed, andheated at 100° C. overnight. The reaction mixture was cooled andpartitioned between ethyl acetate and water. The organic layer was driedover sodium sulphate, filtered and concentrated in vacuo. The residuewas purified by preparative HPLC to give the title compound as a whitesolid (27.3 mg, 28%).

¹H NMR (CDCl₃): δ 9.96 (1H, t, J 5.8 Hz); 8.64 (1H, s); 7.89 (2H, d, J8.3 Hz); 7.82 (1H, d, J 8.0 Hz); 7.75 (1H, t, J 7.9 Hz); 7.56-7.50 (3H,m); 7.46 (1H, d, J 7.8 Hz); 4.69 (2H, ddd, J 22.1, 15.7, 6.2 Hz); 4.43(1H, d, J 2.6 Hz); 4.26 (1H, d, J 2.6 Hz); 3.83 (2H, t, J 6.5 Hz); 3.03(3H, s); 2.11 (3H, s); 1.74 (2H, quintet, J 9.2 Hz); 1.46 (2H, sextet, J9.1 Hz); 0.98 (3H, t, J 7.4 Hz).

APCI-MS m/z: 563 [MH⁺].

b)5-Acetyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

Aqueous hydrochloric acid (2.0M, 50 μl) was added to a solution of5-(1-butoxyvinyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(38 mg, 67.5 μmol) in DMF (0.5 ml). After 20 min. the solution wasneutralized with aqueous sodium hydrogen carbonate. The reaction mixturewas purified by preparative HPLC to give the title compound as a whitesolid (17.6 mg, 51%).

¹H NMR (CDCl₃): δ 9.75 (1H, t, J 5.7 Hz); 9.08 (1H, s); 7.90 (2H, d, J8.3 Hz); 7.85 (1H, d, 7.9 Hz); 7.78 (1H, t, 7.9 Hz); 7.54 (2H, J 8.3Hz); 7.50 (1H, s); 7.42 (1H, J 8.0 Hz); 4.70 (2H, t, J 6.0 Hz); 3.03(3H, s); 2.66 (3H, s); 2.43 (3H, s).

APCI-MS m/z: 507 [MH⁺].

c)5-Bromoacetyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

Bromine (34 μl, 0.66 mmol) in THF (5 ml) was added to a solution of5-acetyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(320 mg, 0.63 mmol) in THF (10 ml). After 2 h, the yellow colour haddisappeared. The reaction mixture was partitioned between water andethyl acetate, the organic phase was separated, evaporated, and theresidue was chromatographed on silica using ethyl acetate/heptane (1/1,2/1, 4/1) as eluent. Fractions containing the product were combined andevaporated to give the title compound (150 mg, 41%).

¹H NMR (CDCl₃): δ 9.67 (1H, t); 9.00 (1H, s); 7.89 (2H, d); 7.86 (1H,d); 7.78 (1H, t); 7.52 (2H, d); 7.50 (1H, s); 7.42 (1H, d); 4.69 (2H,m); 4.41 (2H, s); 3.02 (3H, s); 2.42 (3H, s).

d)6-Methyl-5-(2-methyl-1,3-oxazol-4-yl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

A mixture of5-(bromoacetyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(90 mg, 0.15 mmol) and acetamide (44 mg, 0.75 mmol), xylene (300 μl) andcone. H₂SO₄ (10 μl) was heated with stirring for 3 h. The reaction wasdiluted with water and CH₃CN and purified on preparative HPLC affordingthe title compound (37 mg, 45%).

¹H NMR (CDCl₃): δ 10.08 (1H, t); 8.69 (1H, s); 7.88 (2H, d); 7.82 (1H,d); 7.76 (1H, t); 7.72 (1H, s); 7.54 (1H, s); 7.52 (2H, d); 7.46 (1H,d); 4.69 (2H, m); 3.02 (3H, s); 2.56 (3H, s); 2.19 (3H, s).

APCI-MS m/z: 546.4 [MH⁺].

Example 516-Methyl-N-[4-(methylsulfonyl)benzyl]-5-(1,3-oxazol-4-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

A mixture of5-(bromoacetyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(Example 50 (c), 100 mg, 0.17 mmol), formamide (135 μl, 3.4 mmol),xylene (300 μl) and conc. H₂SO₄ (10 μl) was heated with stirring for 2h. The reaction was diluted with water and CH₃CN and purified onpreparative HPLC, affording the title compound (23 mg, 31%).

¹H NMR (CDCl₃): δ 9.95 (1H, t); 8.75 (1H, s); 7.99 (1H, d); 7.88 (2H,d); 7.86 (1H, d); 7.83 (1H, d); 7.76 (1H, t); 7.72 (1H, s); 7.52 (2H,d); 7.47 (1H, d); 4.69 (2H, m); 3.03 (3H, s); 2.24 (3H, s).

APCI-MS m/z: 523.3 [MH⁺].

Example 525-(2-Amino-thiazol-4-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

5-Bromoacetyl-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide (Example 50 (c), 0.04 g, 0.067 mmol),thiourea (0.0067 g, 0.086 mmol), NaOAc (0.011 g, 0.136 mmol), EtOH (2ml) and a magnetic stirrer bar were placed in a tube designed formicrowave synthesis. The vial was sealed and the mixture was heated in aCEM Discover Microwave apparatus (100 W, 90° C.) for 20 minutes, givingcomplete conversion of the starting material to a single productaccording to LC-MS. The solvents were evaporated to give a crude mixturewhich was purified on preparative HPLC giving the title compound (0.026g, 66%) as a slightly yellowish solid after freeze-drying the purefractions.

¹H NMR (DMSO-d₆): δ 9.92 (1H, t, J 6.1 Hz); 8.64 (1H, s); 7.94 (1H, s);7.90 (1H, d, J 8.0 Hz); 7.87 (2H, d, J 8.3 Hz); 7.81 (1H, d, J 7.7 Hz);7.75 (1H, d, J 7.75 Hz); 7.54 (2H, d, J 8.2 Hz); 7.11 (2H, bs); 6.64(1H, s); 4.65-4.55 (2H, m); 3.17 (3H, s); 2.17 (3H, s).

APCI-MS m/z: 563 [MH⁺].

Example 535-(2,5-Dimethyl-1,3-oxazol-4-yl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide6-Methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-propionyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

A solution of5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(Example 1 (d), 1500 mg, 2.5 mmol),bis[1,2-bis(diphenylphosphino)ethane]palladium(0) (230 mg, 0.25 mmol),triethylamine (7.5 ml, 54 mmol) and ethylpropenyl ether (900 μl, 7.5mmol) in DMF (45 ml) was heated at 100° C. overnight. After cooling, thereaction mixture was poured into water and extracted with ethyl acetateand the solvent was removed under reduced pressure. The crude productwas then dissolved in DMF (25 ml) and 2M HCl (25 ml) and then stirredfor 1.5 h. The reaction mixture was then poured into aqueous NaHCO₃ andextracted with ethyl acetate. The extracts were separated, evaporatedunder reduced pressure, and the residue was chromatographed on silicausing ethyl acetate/heptane (2/1, 4/1, 10/1) as eluent. Fractionscontaining the product were combined and evaporated to give the titlecompound (1.3 g, >99%).

¹H NMR (CDCl₃): δ 9.76 (1H, t); 9.06 (1H, s); 7.89 (2H, d); 7.84 (1H,d); 7.76 (1H, t); 7.52 (2H, d); 7.49 (1H, s); 7.40 (1H, d); 4.68 (2H,m); 3.02 (3H, s); 3.00 (2H, q); 2.39 (3H, s); 1.22 (3H, t).

b)5-(2-Bromopropanoyl)-6-methyl-N-[4-methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

Bromine (84 μl, 1.61 mmol) in THF (5 ml) was added to a solution of6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-propionyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(700 mg, 1.34 mmol) in THF (10 ml). After 2 h, the yellow colour haddisappeared. The reaction mixture was partitioned between water andethyl acetate, the organic phase was separated, dried and evaporatedunder reduced pressure to give the title compound (800 mg, 99%).

¹H NMR (CDCl₃): δ 9.71 (1H, t); 8.97 (1H, d); 7.89 (2H, d); 7.85 (1H,d); 7.77 (1H, t); 7.52 (2H, d); 7.46 (1H, d); 7.40 (1H, d); 5.28 (1H,q); 4.69 (2H, m); 3.02 (3H, s); 2.36 (3H, s); 1.90 (3H, d).

c)5-(2,5-Dimethyl-1,3-oxazol-4-yl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

A mixture of5-(2-bromopropanoyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-(3-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide(130 mg, 0.22 mmol), acetamide (262 mg, 4.4 mmol), xylene (300 μl) andconc. H₂SO₄ (10 μl) was heated with stirring for 2 h. The reaction wasdiluted with water and CH₃CN and purified on preparative HPLC, affordingthe title compound (45 mg, 36%).

¹H NMR (CDCl₃): δ 10.00 (1H, t); 8.54 (1H, s); 7.88 (2H, d); 7.82 (1H,d); 7.75 (1H, t); 7.54 (1H, d); 7.52 (2H, d); 7.47 (1H, d); 4.68 (2H,m); 3.02 (3H, s); 2.51 (3H, s); 2.34 (3H, s); 2.11 (3H, s).

APCI-MS m/z: 560.4 [MH⁺].

Example 546-Methyl-5-(5-methyl-1,3-oxazol-4-yl)-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

A mixture of5-(2-bromopropanoyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(Example 53 (b), 130 mg, 0.22 mmol), formamide (176 μl, 4.4 mmol),xylene (300 μl) and conc. H₂SO₄ (10 μl) was heated with stirring for 2h. The reaction was diluted with water and CH₃CN and purified onpreparative HPLC, affording the title compound (27 mg, 23%).

¹H NMR (CDCl₃): δ 10.02 (1H, t); 8.57 (1H, d); 7.89 (1H, s); 7.88 (2H,d); 7.83 (1H, d); 7.76 (1H, t); 7.55 (1H, d); 7.52 (2H, d); 7.48 (1H,d); 4.69 (2H, m); 3.02 (3H, s); 2.41 (3H, s); 2.09 (3H, s).

APCI-MS m/z: 546.3 [MH⁺].

Example 555-(2-Amino-5-methyl-thiazol-4-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

5-(2-Bromopropanoyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(Example 53 (b), 0.04 g, 0.067 mmol), thiourea (0.0067 g, 0.086 mmol),NaOAc (0.011 g, 0.136 mmol), EtOH (2 ml) and a magnetic stirrer bar wereplaced in a tube designed for microwave synthesis. The vial was sealedand the mixture was heated in a CEM Discover Microwave apparatus (100 W,90° C.) for 20 minutes, giving complete conversion of the startingmaterial to a single product according to LC-MS. The solvents wereevaporated to give a crude mixture which was purified on preparativeHPLC, giving the title compound (0.026 g, 66%) as a slightly yellowishsolid after freeze-drying the pure fractions.

¹H NMR (DMSO-d₆): δ 9.90 (1H, t, J 6.2 Hz); 8.32 (1H, s); 7.98 (1H, s);7.91 (1H, d, J 7.9 Hz); 7.87 (2H, d, J 8.3 Hz); 7.83 (1H, t, J 7.8 Hz);7.77 (1H, d, J 7.8 Hz); 7.54 (2H, d, J 8.2 Hz); 4.67-4.55 (2H, m); 3.18(3H, s); 2.12 (3H, s); 1.91 (3H, s).

APCI-MS m/z: 577.1 [MH⁺].

Example 565-(2-Hydroxymethyl-5-methyl-thiazol-4-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

5-(2-Bromopropanoyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(Example 53 (b), 0.06 g, 0.10 mmol), 2-amino-2-thioxoethyl pivalate(0.022 g, 0.125 mmol), EtOH (2 ml) and a magnetic stirrer bar wereplaced in a tube designed for microwave synthesis. The vial was sealedand the mixture was heated in a CEM Discover Microwave apparatus (100 W,80° C.) for 40 minutes, giving complete conversion of the startingmaterial to a single product according to LC-MS. The solvents wereevaporated to give a crude mixture which was purified on silica giving0.045 g (76%) of the intermediate pivalyl ester. This compound wasdissolved in THF (2 ml) and water (2 ml). To this solution was addedNaOH (0.2 mmol, 0.1 ml of a 2M solution), and the mixture was stirred atroom temperature overnight. The THF was evaporated off and the waterphase was acidified, extracted, and the extracts were evaporated.Purification by preparative HPLC gave pure fractions which werefreeze-dried to give the title compound (0.040 g, 68%) as a white solid.

¹H NMR (DMSO-d₆): δ 9.92 (1H, t, J 6.2 Hz); 8.30 (1H, s); 8.02 (1H, s);7.92-7.88 (1H, d); 7.87 (2H, d, J 8.5 Hz); 7.88-7.78 (2H, m); 7.54 (2H,d, J 8.4 Hz); 6.02 (1H, J 5.8 Hz); 4.69 (2H, d, J 5.8 Hz); 4.64-4.54(2H, m); 3.17 (3H, s); 2.34 (3H, s); 1.89 (3H, s)

APCI-MS m/z: 592.1 [MH⁺].

Example 576-Methyl-5-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide a)5-Cyano-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

A mixture of5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(Example 1 (d), 120 mg, 0.20 mmol) and copper (I) cyanide (66.7 mg, 0.74mmol) in NMP (2.5 ml) was stirred overnight at 140° C. The reactionmixture was cooled and partitioned between ethyl acetate and water. Theorganic layer was dried over sodium sulphate, filtered and concentratedin vacuo. The residue was first purified by preparative HPLC and then byflash chromatography eluting with dichloromethane/methanol (10:0.2) togive the title compound as a white solid (24 mg, 24%).

¹H NMR (DMSO-d₆): δ 9.55 (1H, t, J 6.1 Hz); 8.49 (1H, s); 7.96 (1H, s);7.93 (1H, d, J 7.8 Hz); 7.88-7.81 (3H, m); 7.77 (1H, d, 3″ 8.0 Hz); 7.52(2H, d, J 8.4 Hz); 4.56 (2H, d, J 6.2 Hz); 3.16 (3H, s); 2.22 (3H, s).

APCI-MS m/z: 490 [MH⁺].

b)5-(N-Hydroxycarbamimidoyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

5-Cyano-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(0.040 g, 0.082 mmol), hydroxylamine hydrochloride (0.015 g, 0.209mmol), NaOAc (0.017 g, 0.209 mmol), ethanol (3 ml), water (0.1 ml) and amagnetic stirrer bar were placed in a vial. The mixture was heated (90°C.) overnight. LC-MS showed a 50:50 mixture of two components, one ofwhich had the expected MW. The product was isolated by preparative HPLCgiving 0.012 g (28%) of the intermediate N-hydroxyamidine.

¹H NMR (DMSO-d₆): δ 9.85 (1H, t, J 6.2 Hz); 9.53 (1H, s); 8.33 (1H, s);7.91 (1H, d, J 7.6 Hz); 7.86 (2H, d, J 8.2 Hz); 7.85 (1H, s); 7.83 (1H,t, J 7.8 Hz); 7.69 (1H, d, J 7.8 Hz); 7.54 (2H, d, J 8.3 Hz); 5.88 (2H,bs); 4.64-4.55 (2H, m); 3.17 (3H, s); 2.07 (3H, s).

APCI-MS m/z: 523.2 [MH⁺].

c)6-Methyl-5-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzyl amide

5-(N-Hydroxycarbamimidoyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide (0.011 g, 0.021 mmol), aceticanhydride (0.02 g, 0.195 mmol), toluene (2 ml) and a magnetic stirrerbar were placed in a vial. The vial was sealed and was heated (110° C.)with stirring for 5 h. LC-MS confirmed the consumption of the startingmaterial and the formation of a product with the expected MW.Evaporation and purification on preparative HPLC gave the title compound(0.004 g, 35%) as a white solid after freeze-drying the pure fractions.

¹H NMR (DMSO-d₆): δ 9.77 (1H, t, J 6.2 Hz); 8.90 (1H, s); 8.01 (1H, s);7.93 (1H, d, J 7.5 Hz); 7.87 (2H, d, J 8.3 Hz); 7.87-7.79 (2H, m); 7.55(2H, d, J 8.3 Hz); 7.67-7.53 (2H, m); 3.17 (3H, s); 2.69 (3H, s); 2.37(3H, s).

APCI-MS m/z: 547.2 [MH⁺].

Example 586-Methyl-5-[1,2,4]oxadiazol-3-yl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

5-Cyano-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(Example 57 (a), 0.040 g, 0.082 mmol), hydroxylamine hydrochloride(0.015 g, 0.209 mmol), NaOAc (0.017 g, 0.209 mmol), ethanol (3 ml),water (0.1 ml) and a magnetic stirrer bar were placed in a vial. Themixture was heated (90° C.) overnight. The solvents were evaporated invacuo. The residue was dissolved in triethyl-orthoformate (3 ml) in avial and a magnetic stirrer bar was added. The vial was sealed andheated (130° C.) with stirring for 2 h. LC-MS confirmed formation of aproduct with the expected MW. The volatiles were removed in vacuo, andthe residue was purified on preparative HPLC giving the title compound(0.012 g, 27%) as a white solid after freeze-drying the pure fractions.

¹H NMR (DMSO-d₆): δ 9.78 (1H, s); 9.77 (1H, t, J 6.2 Hz); 8.93 (1H, a);8.03 (1H, s); 7.93 (1H, d, J 7.7 Hz); 7.87 (2H, d, J 8.2 Hz); 7.86-7.80(2H, m); 7.56 (2H, d, J 8.2 Hz); 4.65-4.55 (2H, m); 3.17 (3H, s); 2.39(3H, s).

APCI-MS m/z: 533.2 [MH⁺].

Example 596-Methyl-2-oxo-5-(1H-tetrazol-5-yl)-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

5-Cyano-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide(Example 57 (a), 0.018 g, 0.037 mmol), NaN₃ (0.020 g, 0.307 mmol), NH₄Cl(0.016 g, 0.307 mmol), NMP (1 ml) and a magnetic stirrer bar were placedin a tube designed for microwave synthesis. The vial was sealed and themixture was heated in a CEM Discover Microwave apparatus (100 W, 140°C.) for 30 minutes, giving complete conversion of the nitrile accordingto LC-MS. The crude mixture was dissolved in acetonitrile (2 ml) andwater (2 ml) and was purified directly on preparative HPLC under acidicconditions, giving the title compound (0.012 g, 61%) as a beige solidafter freeze-drying the pure fractions.

¹H NMR (DMSO-d₆): δ 9.81 (1H, t, J 6.1 Hz); 8.79 (1H, bs); 8.02 (1H,bs); 7.93 (1H, d, 7.89 Hz); 7.87 (2H, d, J 8.5 Hz); 7.88-7.85 (1H, m);7.82 (1H, d, J 8.2 Hz); 7.56 (2H, d, J 8.4 Hz); 4.67-4.55 (2H, m); 3.17(3H, s); 2.34 (3H, s).

APCI-MS m/z: 533.2 [MH⁺].

Example 606-Methyl-5-(4-methyl-oxazol-2-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

6-Methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylicacid 5-amide 4-methanesulfonyl-benzylamide [prepared from the acidchloride of5-(4-methanesulfonyl-benzylcarbamoyl)-2-methyl-6-oxo-1-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridine-3-carboxylicacid [described in Example 14 (b)] and ammonia] (0.05 g, 0.098 mmol),1-chloroacetone (0.025 g, 0.27 mmol), CaCO₃ (0.015 g, 0.15 mmol), NMP(1.5 ml) and a magnetic stirrer bar were placed in a tube designed formicrowave synthesis. The vial was sealed and the mixture was heated in aCEM Discover Microwave apparatus (100 W, 155° C.) for 60 minutes, givingcomplete conversion of the amide according to LC-MS. The crude mixturewas dissolved in acetonitrile (2 ml) and water (2 ml) and was purifieddirectly on preparative HPLC giving the title compound (0.006 g, 11%) asa solid after freeze-drying the pure fractions.

¹H NMR (DMSO-d₆): δ 9.79 (1H, t, J 6.1 Hz); 8.89 (1H, s); 7.98 (1H, bs);7.97-7.95 (1H, m); 7.92 (1H, d, J 7.8 Hz); 7.87 (2H, d, J 8.1 Hz); 7.85(1H, t, J 7.9 Hz); 7.79 (1H, d, J 7.9 Hz); 7.55 (2H, d, J 8.2 Hz);4.66-4.55 (2H, m); 3.17 (3H, s); 2.45 (3H, s); 2.17 (3H, s).

APCI-MS m/z: 546.2 [MH⁺].

Example 615-(4,5-Dimethyl-oxazol-2-yl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid 4-methanesulfonyl-benzylamide

6-Methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylicacid 5-amide 4-methanesulfonyl-benzylamide (see Example 60, 0.05 g,0.098 mmol), 3-bromo-2-butanone (0.020 g, 0.20 mmol), CaCO₃ (0.015 g,0.15 mmol), NMP (1.5 ml) and a magnetic stirrer bar were placed in atube designed for microwave synthesis. The vial was sealed and themixture was heated in a CEM Discover Microwave apparatus (100 W, 140°C.) for 2 h. The reaction was stopped and the crude mixture wasdissolved in acetonitrile (2 ml) and water (2 ml) and was purifieddirectly on preparative HPLC, giving the title compound (0.007 g, 13%)as a slightly brownish solid after freeze-drying the pure fractions.

¹H NMR (DMSO-d₆): δ 9.81 (1H, t, J 6.1 Hz); 8.85 (1H, s); 7.98 (1H, bs);7.92 (1H, d, J 7.8 Hz); 7.87 (2H, d, J 8.1 Hz); 7.85 (1H, t, J 7.8 Hz);7.78 (1H, d, J 7.9 Hz); 7.55 (2H, d, J 8.2 Hz); 4.66-4.55 (2H, m); 3.17(3H, s); 2.44 (3H, s); 2.33 (3H, s); 2.17 (3H, s)

APCI-MS m/z: 560.2 [MH⁺].

Example 63N-(Cyclohexylmethyl)-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidea) Ethyl6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate

A suspension of6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid (Example 1 (b), 13.1 g, 43.9 mmol), sodium carbonate (5.2 g, 48.3mmol) and iodoethane (10.6 g, 67.7 mmol) in NMP (60 ml) was stirred atambient temperature for 19 h under a nitrogen atmosphere. The reactionmixture was partitioned between ethyl acetate and water. The organicphase was collected, washed with water and brine, dried over sodiumsulphate, filtered and concentrated in vacuo. The residue was purifiedby flash chromatography on silica eluting with tert-butyl methylether/methanol (10:0.4) to give the title compound as a light brownsolid (12.5 g, 87%).

¹H NMR (CDCl₃): δ 8.21 (1H, d, J 7.4 Hz); 7.75 (1H, d, J 7.8 Hz); 7.68(1H, t, J 7.8 Hz); 7.49 (1H, s); 7.42 (1H, d, J 7.8 Hz); 6.25 (1H, d, J7.4 Hz); 4.36 (2H, q, J 7.2 Hz); 2.03 (3H, s); 1.37 (3H, t, J 7.2 Hz).

APCI-MS m/z: 326.1 [MH⁺].

b) Ethyl5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate

N-Iodosuccinimide (6.89 g, 30.6 mmol) was added to a solution of ethyl6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate(9.9 g, 30.5 mmol) in DCM (45 ml) and TFA (38 ml) under a nitrogenatmosphere. After 19 h stirring at ambient temperature the solvent wasconcentrated in vacuo. Saturated aqueous sodium hydrogen carbonatesolution and ethyl acetate were added to the residue to neutralize theremaining TFA. The organic phase was collected, washed with water andbrine, dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified by flash chromatography on silica eluting withDCM/methanol (10:0.2) to give the title compound as a yellow solid (11.4g, 83%).

¹H NMR (CDCl₃): δ 8.52 (1H, s); 7.76 (1H, d, J 7.8 Hz); 7.69 (1H, t, J7.9 Hz); 7.46 (1H, s); 7.38 (1H, d, J 7.7 Hz); 4.36 (2H, q, J 7.1 Hz);2.26 (3H, s); 1.37 (3H, t, J 7.2 Hz).

APCI-MS m/z: 452.0 [MH⁺].

c) Ethyl6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate

Ethyl5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate(2.6 g, 5.76 mmol), phenyltributylstannane (2.24 mg, 6.10 mmol),tetrakis(triphenylphosphine)palladium(0) (17.3 mg, 0.02 mmol), toluene(15 ml) and anhydrous DME (1.5 ml) were placed in a Schlenk vesselequipped with a magnetic stirring bar. The vessel was purged with argon,sealed and heated at 100° C. overnight. After cooling to roomtemperature, the mixture was partitioned between ethyl acetate andwater. The organic layer was washed with water and brine, dried oversodium sulfate, filtered and concentrated in vacuo. The residue waspurified by preparative HPLC to give the title compound as a white solid(0.8 g, 35%).

¹H NMR (CDCl₃): δ 8.26 (1H, s); 7.72 (2H, m); 7.56 (1H, s); 7.51-7.36(4H, m); 7.34-7.28 (2H, m); 4.37 (2H, q, J 7.1 Hz); 1.97 (3H, s); 1.37(3H, t).

APCI-MS m/z: 402.3 [MH⁺].

d)6-Methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid

Aqueous 2M sodium hydroxide solution (2.5 ml, 5.0 mmol) was added to asolution of ethyl6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate(0.85 g, 2.12 mmol) in THF (5 ml), methanol (3 ml) and water (1 ml). Thereaction mixture was stirred at room temperature for 2 h and thenconcentrated in vacuo. Acetonitrile (3 ml) was added to the residue andthe solution was acidified using TFA. The resulting solid was collectedby filtration, washed with water and acetone and air dried to give thetitle compound as white solid (0.62 g, 78%).

¹H NMR (CDCl₃): δ 13.75 (1H, s); 8.59 (1H, s); 7.87 (1H, d, J 8.1 Hz);7.80 (1H, t, J 7.9 Hz); 7.61 (1H, s); 7.54 (1H, d, J 7.6 Hz); 7.51-7.40(3H, m); 7.31 (2H, m); 2.08 (3H, s).

APCI-MS m/z: 374.2 [MH⁺].

e)N-(Cyclohexyl-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

(Cyclohexylmethyl)amine in NMP (135 μl, 0.3M, 0.04 mmol) was added to amixture of6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydro-pyridine-3-carboxylicacid (12 mg, 0.03 mmol), HATU (15 mg, 0.04 mmol), HOAT (7 mg, 0.04 mmol)and DIEA (13 mg, 0.1 mmol) in NMP (160 μl). The reaction mixture wasstirred for 17 h at room temperature. The solvent was removed in vacuo,and the residue was dissolved in acetonitrile/water, 50/50, to a totalvolume of 1.6 ml, and purified using preparative HPLC to give the titlecompound (7 mg, 50%).

RT (C₁₈, UV 220 nm): 7.0 min.

APCI-MS m/z: 469.1 [MH⁺].

Using the general procedure described in Example 63 and the appropriateamine, the compounds of Examples 64 to 90 were prepared.

Example 646-Methyl-N-(2-morpholin-4-ylethyl)-2-oxo-5-phenyl-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 4.6 min.

APCI-MS m/z: 486.2 [MH⁺].

Example 656-Methyl-2-oxo-5-phenyl-N-(1H-1,2,4-triazol-3-yl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 5.2 min.

APCI-MS m/z: 440.2 [MH⁺].

Example 66N-[2-(1H-Indol-3-yl)ethyl]-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 6.5 min.

APCI-MS m/z: 516.2 [MH⁺].

Example 676-Methyl-2-oxo-5-phenyl-N-(1-phenylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 6.8 min.

APCI-MS m/z: 477.2 [MH⁺].

Example 686-Methyl-2-oxo-5-phenyl-N-(2-phenylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 6.7 min.

APCI-MS m/z: 477.2 [MH⁺].

Example 696-Methyl-2-oxo-5-phenyl-N-[(2R)-2-phenylcyclopropyl]-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 6.9 min.

APCI-MS m/z: 489.2 [MH⁺].

Example 70N-(2,3-Dihydro-1H-inden-2-yl)-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 6.8 min.

APCI-MS m/z: 489.2 [MH⁺].

Example 71N-[(1-Ethylpyrrolidin-2-yl)methyl]-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoro-methyl)phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C_(H), UV 220 nm): 4.7 min.

APCI-MS m/z: 484.2 [MH⁺].

Example 726-Methyl-N-(1-naphthylmethyl)-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 7.0 min.,

APCI-MS m/z: 513.2 [MH⁺].

Example 73N-(1,3-Benzodioxol-5-ylmethyl)-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3carboxamide

RT (C₁₈, UV 220 nm): 6.5 min.

APCI-MS m/z: 507.2 [MH⁺].

Example 74N-(2-Chloro-4-fluorobenzyl)-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 7.0 min.

APCI-MS m/z: 515.2 [MH⁺].

Example 756-Methyl-2-oxo-5-phenyl-N-(2-thienylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 6.5 min.

APCI-MS m/z: 469.1 [MH⁺].

Example 76N-(2-Cyclohex-1-en-1-ylethyl)-6-methyl-2-oxo-5-phenyl-1-[3-trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 7.2 min.

APCI-MS m/z: 481.3 [MH⁺].

Example 776-Methyl-2-oxo-N-(4-phenoxybenzyl)-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 7.3 min.

APCI-MS m/z: 555.2 [MH⁺].

Example 78N-[(2,5-Dimethyl-3-furyl)methyl]-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoro-methyl)phenyl]-1,2-dihydropyridine-3-carboxamide

APCI-MS m/z: 481.4 [MH⁺].

Example 79N-{2-[4-(Aminosulfonyl)phenyl]ethyl}-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoro-methyl)phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 5.8 min.

APCI-MS m/z: 556.1 [MH⁺].

Example 806-Methyl-2-oxo-5-phenyl-N-[4-1H-pyrazol-1-yl)benzyl]-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 6.4 min.

APCI-MS m/z: 529.1 [MH⁺].

Example 816-Methyl-2-oxo-N-phenoxy-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydro-pyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 6.6 min.

APCI-MS m/z: 465.1 [MH⁺].

Example 82N-[(6-Fluoro-4H-1,3-benzodioxin-8-yl)methyl]-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 6.6 min.

APCI-MS m/z: 539.2 [MH⁺].

Example 836-Methyl-2-oxo-5-phenyl-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]-1-[3-(trifluoro-methyl)phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 6.0 min.

APCI-MS m/z: 485.2 [MH⁺].

Example 846-Methyl-2-oxo-5-phenyl-N-[3-(1H-pyrazol-1-yl)propyl]-1-[3-trifluoromethyl-phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 5.7 min.

APCI-MS m/z: 481.1 [MH⁺].

Example 856-Methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-oxo-5-phenyl-1-[3-trifluoro-methyl)phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 5.4 min.

APCI-MS m/z: 467.2 [MH⁺].

Example 866-Methyl-2-oxo-5-phenyl-N-[(1-phenyl-1H-pyrazol-4-yl)methyl]-1-[3-(trifluoro-methyl)phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 6.5 min.

APCI-MS m/z: 529.1 [MH⁺].

Example 87N-[(5-Methoxy-4-oxo-4H-pyran-2-yl)methyl]-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 5.4 min.

APCI-MS m/z: 511.1 [MH⁺].

Example 88N-(3-Azepan-1-ylpropyl)-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 5.0 min.

APCI-MS m/z: 512.3 [MH⁺].

Example 89N-(4-Cyanobenzyl)-6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 6.4 min.

APCI-MS m/z: 488.2 [MH⁺].

Example 906-Methyl-2-oxo-N-[3-(5-oxo-4,5-dihydro-1H-pyrazol-4-yl)propyl]-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

RT (C₁₈, UV 220 nm): 5.0 min.

APCI-MS m/z: 497.2 [MH⁺].

Example 916-Methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid (3-methyl-isoxazol-5-ylmethyl)-amide a)6-Methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid prop-2-ynylamide

SOCl₂ (10 ml) was added in one portion to a solution of6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid (Example 1 (b), 1.0 g, 3.36 mmol) in DCM (10 ml). The solution wasstirred magnetically for 1 h at which time LC-MS showed completeconversion. The crude mixture was evaporated in vacuo, giving theintermediate acid chloride as a yellow solid. This solid was dissolvedin 1,4-dioxane (10 ml, dried over molecular sieves) and propargylamine(0.23 g, 4.17 mmol) and triethylamine (1 ml) were added. The mixture wasstirred for 10 minutes, and LC-MS showed complete formation of theproduct. The mixture was concentrated in vacuo and the residue waspurified on silica giving the subtitle compound (0.93 g, 83%) as ayellowish solid after evaporating the pure fractions.

¹H NMR (DMSO-d₆): δ 9.82 (1H, t, J 7.4 Hz); 8.36 (1H, d, J 7.7 Hz); 7.91(1H, s); 7.90 (1H, d); 7.82 (1H, t, J 8.1 Hz); 7.73 (1H, d, J 8.1 Hz);6.63 (1H, d, J 7.5 Hz); 4.10-4.04 (2H, m); 3.11 (1H, t, J 2.4 Hz); 2.02(3H, s).

APCI-MS m/z: 335.1 [MH⁺].

b)6-Methyl-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylicacid (3-methyl-isoxazol-5-ylmethyl)-amide

The compound obtained in step (a) (0.050 g, 0.15 mmol) was dissolved inEtOAc (15 ml) under magnetic stirring. To this solution was addedN-hydroxyacetimidoyl chloride (0.15 g, 1.6 mmol), water (0.3 ml) andKHCO₃ (0.16 g, 1.6 mmol). The mixture was stirred for 2 days at whichtime LC-MS showed 90% conversion. The reaction was stopped and themixture was partitioned between EtOAc (25 ml) and water (25 ml). Theorganic phase was washed (water, brine) and dried. Filtration andevaporation gave a crude mixture which was purified by chromatography onsilica. Freeze-drying the pure fractions afforded the subtitle compound(0.031 g, 53%) as a white powder.

¹H NMR (DMSO-d₆): δ 9.86 (1H, t, J 5.9 Hz); 8.37 (1H, d, j 7.6 Hz); 7.91(1H, s); 7.90 (1H, d); 7.81 (1H, t, J 7.9 Hz); 7.72 (1H, d, J 7.7 Hz);6.63 (1H, d, J 7.6 Hz); 6.15 (1H, s); 4.58 (2H, d, 5.9 Hz); 2.17 (3H,s); 2.03 (3H, s).

APCI-MS m/z: 392.2.2 [MH⁺].

c)6-Methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid (3-methyl-isoxazol-5-ylmethyl)-amide

The compound obtained in step (b) (0.019 g, 0.048 mmol) was dissolved inDCM (1.5 ml) and TFA (1.5 ml). A magnetic stirrer bar andN-iodosuccinimide (0.011 g, 0.048 mmol) were added and the vial wassealed and stirred for 90 minutes at room temperature. LC-MS showedcomplete conversion of the starting material. The volatiles were removedin vacuo and the crude material was purified on silica, giving the5-iodinated intermediate (0.014 g). This intermediate was dissolved inDME (2.5 ml) in a vial, and 5-trimethylstannyl-1-methyl-1H-pyrazole(0.02 g, 0.082 mmol) and Pd(PPh₃)₄ (0.010 g, 8.7 mol) were added. Thevial was sealed and the mixture was heated (130° C.) with stirring for 1h. LC-MS now showed complete conversion of the iodide to a product withthe expected MW. Evaporation and purification by preparative HPLCafforded the title compound (0.008 g, 35%, two steps) as a white solidafter freeze-drying the pure fractions.

¹H NMR (DMSO-d₆): δ 9.82 (1H, t, J 6.0 Hz); 8.21 (1H, s); 8.02 (1H, s);7.92 (1H, d, J 7.6 Hz); 7.88-7.78 (2H, m); 7.53 (1H, d, J 1.9 Hz); 6.33(1H, d, J 1.9 Hz); 6.16 (1H, s); 4.60 (2H, d, J 6.1 Hz); 3.72 (3H, s);2.17 (3H, s); 1.82 (3H, s).

APCI-MS m/z: 472.1 [MH⁺].

Example 926-Methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid (5-methanesulfonylmethyl-[1,2,4]oxadiazol-3-ylmethyl)-amide a)6-Methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-1-(5-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid

Ethyl5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate(Example 63 (b), 0.77 g, 1.7 mmol), DME (25 ml),5-trimethylstannyl-1-methyl-1H-pyrazole (0.49 g, 2 mmol), Pd(PPh₃)₄(0.10 g, 0.087 mmol) and a magnetic stirrer bar were placed in apressure safe glass vessel. The vessel was sealed and heated (130° C.)with stirring overnight. LC-MS showed complete formation of the product.The mixture was allowed to cool, and was then diluted with EtOAc (50ml), washed with water and brine, and further dried with Na₂SO₄.Filtration and evaporation and subsequent purification on silica gavethe intermediate ester. This material was dissolved in THF (10 ml) andwater (5 ml) and NaOH (2M, 1 ml, 2 mmol) was added. The mixture wasstirred at 50° C. for 1 h. The TIM was evaporated off and the aqueoussolution was acidified whereupon the product precipitated. The productwas extracted with EtOAc. The extracts were dried (Na₂SO₄) andevaporated to give the carboxylic acid (0.3 g, 47%) as yellowish solid.

¹H NMR (DMSO-d₆): δ 13.80 (1H, s); 8.25 (1H, s); 8.07 (1H, s); 7.99-7.93(1H, m); 7.90-7.85 (2H, m); 7.54 (1H, d, J 1.8 Hz); 6.36 (1H, d, J 1.8Hz); 3.73 (3H; s); 1.86 (3H, s).

APCI-MS m/z: 363.3 [MH⁺].

b)6-Methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid cyanomethyl amide

The compound obtained in step (a) (0.2 g, 0.53 mmol) was dissolved in1,4-dioxane (5 ml), HBTU (0.19 g, 0.5 mmol) and DMA (0.32 g, 2.5 mmol).The mixture was stirred for 10 minutes and aminoacetonitrilehydrochloride (0.55 g, 0.6 mmol) was added. After 1 h the mixture wasevaporated and the residue purified by chromatography on silica to givethe amide (0.15 g, 72%) as a white solid.

¹H NMR (DMSO-d₆): δ 9.75 (1H, t, J 5.9 Hz); 8.22 (1H, s); 8.03 (1H, s);7.93 (1H, d, J 7.25 Hz); 7.88-7.81 (2H, m); 7.54 (1H, d, J 1.8 Hz); 6.34(1H, d, J 1.8 Hz); 4.31 (2H, d, J 5.9 Hz); 3.72 (3H, s); 1.83 (3H, s).

APCI-MS m/z: 416.2 [MH⁺]. Retention time 2.2 minutes.

c)6-Methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylicacid (N-hydroxycarbamimidoylmethyl)-amide

The compound obtained in step (b) (0.21 g, 0.5 mmol), hydroxylaminehydrochloride (0.070 g, 1 mmol), NaOAc (0.080 g, 1 mmol), EtOH (2 ml)and a magnetic stirrer bar were placed in a vial. The vial was sealedand the mixture was heated (90° C.) with stirring for 3 h. LC-MS showedcomplete conversion of the nitrile into a mixture of two compounds withthe masses 449 and 465 ([MH⁺]). Evaporation and purification onpreparative HPLC gave a mixture of the two products containing 90% ofthe desired compound. This material was used without furtherpurification.

APCI-MS m/z: 449.2 [MH⁺].

d)6-Methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-1-(3-trifluoromethylphenyl)-1,2-dihydro-pyridine-3-carboxylicacid (5-methanesulfonylmethyl-[1,2,4]oxadiazol-3-ylmethyl)-amide

The compound obtained in step (c) (0.019 g, 0.042 mmol) was dissolved in1,4-dioxane (dry, 1 ml) and CH₃CN (dry, 1 ml) in a vial.2-Methanesulfonylacetylchloride (prepared according to literatureprocedures, 0.015 g, 0.095 mmol) was added, the vial was sealed and themixture was stirred at room temperature for 1 h. Isolation of thismaterial and purification by preparative HPLC gave, after freeze-drying,the required intermediate (0.011 g). This solid was dissolved in1,4-dioxane (2 ml) in a vial and acetic acid (5 drops) was added. Thevial was sealed and the mixture was heated (90° C.) with stirring for 5h (monitoring the reaction by LC-MS). When reaction was complete, themixture was allowed to cool and the volatiles were removed in vacuo. Thecrude mixture was purified by preparative HPLC to give the titlecompound (0.008 g, 35%, 2 steps) as a white solid after freeze-dryingthe pure fractions.

¹H NMR (DMSO-d₆): δ 9.93 (1H, t, J 6.0 Hz); 8.21 (1H, s); 8.04 (1H, s);7.93 (1H, d, J 7.93 Hz); 7.88-7.82 (2H, m); 7.53 (1H, d, J 1.9 Hz); 6.33(1H, d, J 1.9 Hz); 5.18 (2H, s); 4.70 (2H, d, J 6.0 Hz); 3.72 (3H, s);3.19 (3H, s); 1.83 (3H, s).

APCI-MS m/z: 551.2 [MH⁺].

Example 936-Methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid ([1,2,4]oxadiazol-3-ylmethyl)-amide

6-Methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid (N-hydroxycarbamimidoylmethyl)-amide (Example 92 (c), 0.017 g,0.038 mmol), triethyl-orthoformate (1 ml) and a magnetic stirrer barwere placed in a vial. The vial was sealed and the mixture was heated(130° C.) with stirring for 3 h. LC-MS showed complete conversion of thestarting material to a product with the expected MW. The volatiles wereremoved in vacuo and the residue was purified by preparative HPLC. Purefractions were freeze-dried to give the title compound (0.009 g, 53%) asa white solid.

¹H NMR (DMSO-d₆): δ 9.92 (1H, t, J 5.9 Hz); 9.54 (1H, s); 8.21 (1H, s);8.03 (1H, s); 7.93 (1H, d, J 7.0 Hz); 7.88-7.82 (2H, m), 7.53 (1H, d, J1.8 Hz); 6.33 (1H, d, J 1.8 Hz); 4.69 (2H, d, J 5.9 Hz); 3.72 (3H, s);1.83 (3H, s).

APCI-MS m/z: 459.1 [MH⁺].

Example 946-Methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-methyl}-2-oxo-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidea) 5-(Methylthio)pyridine-2-carbonitrile

5-Bromo-pyridine-2-carbonitrile (2.63 g, 13.7 mmol), sodiummethanethiolate (1.44 g, 20.5 mmol), potassium carbonate (3.79 g, 27.4mmol) in NMP (60 ml) were stirred in a sealed flask overnight. Themixture was partitioned between ethyl acetate and water. The organicphase was washed with water several times, brine and dried over sodiumsulphate. The solvent was removed in vacuo to afford the title compoundas a yellow solid (2.0 g, 99%).

¹H NMR (CD₃OD): δ 8.54 (1H, d, J 2.3 Hz); 7.83-7.71 (2H, m); 2.60 (3H,s).

b) 5-(Methylsulfonyl)pyridine-2-carbonitrile

5-(Methylthio)pyridine-2-carbonitrile (2.0 g, 13.3 mmol) was dissolvedin DCM (20 ml) and cooled to −15° C. and 3-chloroperoxybenzoic acid(6.75 g, 27.4 mmol) was added in portions while the temperature was keptbetween −15° C. to −10° C. When the addition was complete, the coolingbath was removed and the mixture was stirred at room temperature for 2h. 2M KOH and DCM were added. The organic phase was separated, washedtwice with 2M KOH, water and brine, dried over sodium sulphate andevaporated to afford the title compound as a white solid (2.15 g, 89%).

¹H NMR (CD₃OD): δ 9.22 (1H, d, J 2.3 Hz); 8.54 (1H, dd, J 8.1, 2.3 Hz);8.13 (1H, d, J 8.3 Hz); 3.27 (3H, s).

c) {[5-(Methylsulfonyl)pyridin-2-yl]methyl}amine hydrochloride

5-(Methylsulfonyl)pyridine-2-carbonitrile (2.15 g, 11.8 mmol) wasdissolved in methanol (230 ml). 6M HCl (1 ml) and 10% palladium oncarbon (2.34 mg) were added and the mixture was stirred under anatmospheric pressure of hydrogen overnight. The catalyst was removed byfiltration through celite and the solvent was evaporated, water wasadded and the solution was freeze-dried to afford the title compound asa yellow powder (2.34 g, 89%).

¹H NMR (CD₃OD); δ 9.10 (1H, d, J 2.2 Hz); 8.36 (1H, dd, J 8.2, 2.4 Hz);7.68 (1H, d, J 8.8 Hz); 4.29 (2H, s); 3.22 (3H, s).

d)6-Methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

HBTU (30 mg, 0.079 mmol) was added to{[5-(methylsulfonyl)pyridin-2-yl]methyl}amine hydrochloride (20 mg,0.090 mmol),6-methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylicacid (Example 92 (a), 27 mg, 0.072 mmol) and DMA (23 μl, 0.31 mmol) inNMP (0.25 ml) and the mixture was stirred in a sealed vial overnight.The product was purified by preparative HPLC and freeze-dried to givethe title compound as a white solid (8 mg, 20%).

¹H NMR (CD₃OD): δ 9.01 (1H, d, J 2.2 Hz); 8.37 (1H, s); 8.28 (1H, dd, J8.4, 2.3 Hz); 7.93-7.80 (3H, m); 7.73-7.60 (2H, m); 7.57 (1H, d, J 2.0Hz); 6.38 (1H, d, J 2.0 Hz); 4.83 (2H, s); 3.79 (3H, s); 3.18 (3H, s);1.94 (3H, s).

APCI-MS m/z: 546.1 [MH⁺].

Example 955-(3,5-Dimethylisoxazol-4-yl)-6-methyl-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamidea)5-(3,5-Dimethylisoxazol-4-yl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid

Ethyl5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate(Example 63 (b), 0.72 g, 1.6 mmol), DME (20 ml),3,5-dimethylisoxazolyl-4-boronic acid (0.28 g, 2 mmol), Pd₂(dba)₃ (0.036g, 0.039 mmol), PPh₃ (0.062 g, 0.23 mmol), 2M Na₂CO₃ (10 ml) and amagnetic stirrer bar were placed in a pressure safe glass vessel. Thevessel was sealed and heated (120° C.) with stirring overnight. LC-MSshowed complete formation of the required product (including hydrolysisof the ester). The mixture was allowed to cool, the aqueous phase wasacidified, and the organic phase was diluted with EtOAc (50 ml) and thephases were allowed to separate. The organic phase was washed with waterand brine, and further dried with Na₂SO₄. Filtration and evaporationgave a crude mixture which was purified by preparative HPLC giving thecarboxylic acid (0.27 g, 43%) as yellowish solid.

¹H NMR (DMSO-d₆): δ 13.93 (1H, s); 8.25 (1H, s); 8.07 (1H, s); 7.99-7.93(1H, m); 7.89-7.85 (2H, m); 2.35 (3H, m); 2.15-2.10 (3H, m); 1.85 (3H,s).

APCI-MS m/z: 393.1 [MH⁺].

b)5-(3,5-Dimethylisoxazol-4-yl)-6-methyl-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide

The title compound was prepared from5-(3,5-dimethylisoxazol-4-yl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylicacid using a method analogous to that described in Example 94.

¹H NMR (CD₃OD): δ 9.01 (1H, d, J 1.8 Hz); 8.31 (1H, s); 8.28 (1H, dd, J8.2, 2.4 Hz); 7.92-7.80 (3H, m); 7.70 (1H, d, J 7.9 Hz); 7.62 (1H, d, J8.2 Hz); 4.82 (2H, s); 3.18 (3H, s); 2.34 (3H, d, J 2.2 Hz); 2.18 (3H,d, J 2.0 Hz); 1.93 (3H, s).

APCI-MS m/z: 561.1 [MH⁺].

Screen Human Neutrophil Elastase Quenched-FRET Assay

The assay uses Human Neutrophil Elastase (FINE) purified from serum(Calbiochem art. 324681; Ref. Baugh, R. J. et al., 1976, Biochemistry.15, 836-841). HNE was stored in 50 mM NaOAc, 200 mM NaCl, pH 5.5 withadded 30% glycerol at −20° C. The protease substrate used was ElastaseSubstrate V Fluorogenic, MeOSuc-AAPV-AMC (Calbiochem art. 324740; Ref.Castillo, M. J. et al., 1979, Anal. Biochem. 99, 53-64). The substratewas stored in DMSO at −20° C. The assay additions were as follows: Testcompounds and controls were added to black 96-well flat-bottom plates(Greiner 655076), 1 μL in 100% DMSO, followed by 30 μL HNE in assaybuffer with 0.01% TritonX-100. The assay buffer constitution was: 100 mMTris (pH 7.5) and 500 mM NaCl. The enzyme and the compounds wereincubated at room temperature for 15 minutes. Then 30 μl substrate inassay buffer was added. The assay was stopped after 30 minutesincubation at room temperature by adding 60 μl stop solution (140 mMacetic acid, 200 mM sodium monochloroacetate, 60 mM sodium acetate, pH4.3). Fluorescence was measured on a Wallac 1420 Victor 2 instrument atsettings: Excitation 380 nm, Emission 460 nm. IC₅₀ values weredetermined using Xlfit curve fitting using model 205.

When tested in the above screen, the compounds of the Examples gave IC₅₀values for inhibition of human neutrophil elastase activity of less than30 μM, indicating that the compounds of the invention are expected topossess useful therapeutic properties. Specimen results are shown in thefollowing Table:

Inhibition of Human Neutrophil Elastase Compound IC₅₀ (nM) Example 2 46Example 5 48 Example 1 47 Example 32 3 Example 36 17 Example 46 7Example 91 12

1. A compound of formula (I)

wherein: Y represents CR³ or N; R¹ represents H or C1 to 6 alkyl; R²represents phenyl or a five- or six-membered heteroaromatic ringcontaining 1 to 4 heteroatoms independently selected from O, S and N;said aromatic ring being optionally substituted by 1 to 3 substituentsselected independently from OH, halogen, C1 to 6 alkyl, C1 to 6 alkoxy,NR⁵⁸COR⁵⁰, COOR⁵¹, COR⁵², CONR⁵³R⁵⁴ and NR⁴⁷R⁴⁸; said alkyl beingoptionally further substituted by OH, C1 to 6 alkoxy, CN or CO₂R⁴⁹; R⁴⁷and R⁴⁸ independently represent H, C1 to 6 alkyl or C2 to 6 alkanoyl; R³represents H or F; G¹ represents phenyl or a five- or six-memberedheteroaromatic ring containing 1 to 3 heteroatoms independently selectedfrom O, S and N; R⁵ represents H, halogen, C1 to 6 alkyl, CN, C1 to 6alkoxy, NO₂, NR¹⁴R¹⁵, C1 to 3 alkyl substituted by one or more F atomsor C1 to 3 alkoxy substituted by one or more F atoms; R¹⁴ and R¹⁵independently represent H or C1 to 3 alkyl; said alkyl being optionallyfurther substituted by one or more F atoms; n represents an integer 1, 2or 3 and when n represents 2 or 3, each R⁵ group is selectedindependently; R⁴ represents H or C1 to 6 alkyl; said alkyl beingoptionally further substituted by OH or C1 to 6 alkoxy; or R⁴ and L arejoined together such that the group —NR⁴L represents a 5 to 7 memberedazacyclic ring optionally incorporating one further heteroatom selectedfrom O, S and NR¹⁶; L represents a bond, O, S(O)p, NR²⁹ or C1 to 6alkyl; said alkyl optionally incorporating a heteroatom selected from O,S and NR¹⁶; and said alkyl being optionally further substituted by OH orOMe; G² represents a monocyclic ring system selected from: i) phenyl orphenoxy, ii) a 5 or 6 membered heteroaromatic ring containing one tothree heteroatoms independently selected from O, S and N, iii) a C3 to 6saturated or partially unsaturated cycloalkyl, or iv) a C4 to 7saturated or partially unsaturated heterocyclic ring containing one ortwo heteroatoms independently selected from O, S(O)_(p) and NR¹⁷ andoptionally further incorporating a carbonyl group; or G² represents abicyclic ring system in which each of the two rings is independentlyselected from: i) phenyl, ii) a 5 or 6 membered heteroaromatic ringcontaining one to three heteroatoms independently selected from O, S andN, iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or iv)a C4 to 7 saturated or partially unsaturated heterocyclic ringcontaining one or two heteroatoms independently selected from O,S(O)_(p) and NR¹⁷ and optionally further incorporating a carbonyl group;and the two rings are either fused together, or are bonded directlytogether or are separated by a linker group selected from O, S(O)_(q) orCH₂, said monocyclic or bicyclic ring system being optionally furthersubstituted by one to three substituents independently selected from CN,OH, C1 to 6 alkyl, C1 to 6 alkoxy, halogen, NR¹⁸R¹⁹, NO₂, OSO₂R³⁸,CO₂R²⁰, C(═NH)NH₂, C(O)NR²¹R²², C(S)NR²³R²⁴, SC(═NH)NH₂, NR³¹C(═NH)NH₂,S(O)_(s)R²⁵, SO₂NR²⁶R²⁷, C1 to 3 alkoxy substituted by one or more Fatoms and C1 to 3 alkyl substituted by SO₂R³⁹, NR⁵⁶R⁵⁷ or by one or moreF atoms; or when L does not represent an bond, G² may also represent H;At each occurrence, p, q, s and t independently represent an integer 0,1 or 2; R¹⁸ and R¹⁹ independently represent H, C1 to 6 alkyl, formyl, C2to 6 alkanoyl, S(O)_(t)R³² or SO₂NR³³R³⁴; said alkyl group beingoptionally further substituted by halogen, CN, C1 to 4 alkoxy orCONR⁴¹R⁴²; R²⁵ represents H, C1 to 6 alkyl or C3 to 6 cycloalkyl; saidalkyl group being optionally further substituted by one or moresubstituents selected independently from OH, CN, CONR³⁵R³⁶, CO₂R³⁷,OCOR⁴⁰, C3 to 6 cycloalkyl, a C4 to 7 saturated heterocyclic ringcontaining one or two heteroatoms independently selected from O,S(O)_(p) and NR⁴³ and phenyl or a 5 or 6 membered heteroaromatic ringcontaining one to three heteroatoms independently selected from O, S andN; said aromatic ring being optionally further substituted by one ormore substituents selected independently from halogen, CN, C1 to 4alkyl, C1 to 4 alkoxy, OH, CONR⁴⁴R⁴⁵, CO₂R⁴⁶, S(O)_(s)R⁵⁵ and NHCOCH₃;R³² represents H, C1 to 6 alkyl or C3 to 6 cycloalkyl; R¹⁶, R¹⁷, R²⁰,R²¹, R²², R²³, R²⁴, R²⁶, R²⁷, R²⁹, R³¹, R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸,R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴,R⁵⁵, R⁵⁶, R⁵⁷ and R⁵⁸ independently represent H or C1 to 6 alkyl; andpharmaceutically acceptable salts thereof.
 2. A compound of formula (I),according to claim 1, wherein Y represents CR³.
 3. A compound of formula(I), according to claim 1, wherein G¹ represents phenyl.
 4. A compoundof formula (I), according to claim 1, wherein R⁵ represents Cl, CH₃, CNor CF₃.
 5. A compound of formula (I), according to claim 1, or apharmaceutically acceptable salt thereof, for use as a medicament.
 6. Apharmaceutical formulation comprising a compound of formula (I), asdefined in claim 1, or a pharmaceutically acceptable salt thereof,optionally in admixture with a pharmaceutically acceptable diluent orcarrier.
 7. A method of treating, or reducing the risk of, a humandisease or condition in which inhibition of neutrophil elastase activityis beneficial which comprises administering to a person suffering fromor susceptible to such a disease or condition, a therapeuticallyeffective amount of a compound of formula (I), as defined in claim 1, ora pharmaceutically acceptable salt thereof.
 8. The use of a compound offormula (I) as defined in claim 1, or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for the treatment orprophylaxis of human diseases or conditions in which inhibition ofneutrophil elastase activity is beneficial.
 9. The use of a compound offormula (I) as defined in claim 1, or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for the treatment orprophylaxis of inflammatory diseases or conditions.
 10. A process forthe preparation of a compound of formula (I), as defined in claim 1, andoptical isomers, racemates and tautomers thereof and pharmaceuticallyacceptable salts thereof, which comprises: a) reacting a compound offormula (II)

wherein R¹, R⁴, R⁵, Y, G¹, G², L and n are as defined in formula (I) andHal represents a halogen atom, preferably bromo or iodo; with anucleophile R²-M wherein R² is as defined in formula (I) and Mrepresents an organo-tin or organo boronic acid group; or b) when R²represents a 1,3,4-oxadiazol-2-yl or a 1,3,4-thiadiazol-2-yl ring,reacting a compound of formula (III)

wherein R¹, R⁴, R⁵, Y, G¹, G², L and n are as defined in formula (I), Zrepresents O or S and X represents C1 to 6 alkyl or NR⁴⁷R⁴⁸ and R⁴⁷ andR⁴⁸ are as defined in formula (I); with a suitable dehydrating agentsuch as phosphoryl chloride or trimethylsilyl polyphosphate; or c)reacting a compound of formula (XV)

wherein R¹, R², R⁵, n, G¹ and Y are as defined in formula (I) and L¹represents a leaving group, with a compound of formula (IX) or a saltthereof

wherein R⁴, G² and L are as defined in formula (I); and where desired ornecessary converting the resultant compound of formula (I), or anothersalt thereof, into a pharmaceutically acceptable salt thereof; orconverting one compound of formula (I) into another compound of formula(I); and where desired converting the resultant compound of formula (I)into an optical isomer thereof.